Pharmaceutically active compounds

ABSTRACT

There is provided compounds of formula IA and of formula IB,                    
     wherein R 1 , R 2 , R 3 , Het 1  and X have meanings given in the description, which are useful in the curative and prophylactic treatment of medical conditions for which inhibition of a cyclic guanosine 3′,5′-monophosphate phosphodiesterase (e.g. cGMP PDE5) is desired.

This application is a divisional of U.S. patent application Ser. No.09/650,848 filed Aug. 29, 2000, now U.S. Pat. No. 6,440,982 which claimsthe benefit of U.K. Provisional Patent Application No. 9924020.2 filedOct. 11, 1999.

FIELD OF THE INVENTION

This invention relates to pharmaceutically useful compounds, inparticular compounds which are useful in the inhibition of cyclicguanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs), such astype 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMPPDE5). The compounds therefore have utility in a variety of therapeuticareas, including male erectile dysfunction (MED).

PRIOR ART

Certain purinone derivatives for use in inhibition of cGMP PDEs aredisclosed in European patent applications EP 722943, EP 722944, EP293063 and EP 352960, international patent applications WO 96/16657 andWO 94/00453, German patent application DE 19702785 and Japanese patentapplication JP 63196585. Further, EP 675124 discloses purine derivativesfor use as anti-inflammatory agents.

DISCLOSURE OF THE INVENTION

According to a first aspect of the invention there is provided compoundsof formulae IA and IB,

wherein

X represents CH or N;

R¹ represents H, —CN, —C(O)N(R⁴)R⁵, —C(O)R⁴, —C(O)OR⁴, —N(R⁴)R⁶, —OR⁷,aryl, Het² or lower alkyl (which alkyl group is optionally interruptedby one or more of —O—, —S— or —N(R⁴)— and/or substituted and/orterminated by one or more substituents selected from halo, —CN, —NO₂,lower alkyl, —C(O)N(R⁴)R⁵, —C(O)R⁴, —C(O)OR⁴, —N(R⁴)R⁶, —OR⁷,—S(O)_(n)R⁴, —S(O)_(n)N(R⁴)R⁵, aryl and Het²);

R⁶ represents R⁵, —S(O)₂R⁸, —S(O)₂N(R⁴)R⁵, —C(O)R⁴, —C(O)OR⁸ or—C(O)N(R⁴)R⁵;

R⁷ represents R⁴ or —C(O)R⁴;

R³, R⁴, R⁵ and R⁸ independently represent, at each occurrence when usedherein, lower alkyl, which alkyl group is optionally substituted and/orterminated by one or more substituents selected from lower alkyl, aryl,Het³, halo, —CN, —NO₂, —OR^(9a), —C(O)R^(9b), —C(O)OR^(9c),—C(O)N(R^(9d))R^(9e), —S(O)₂R^(10a), —S(O)₂N(R^(9f))R^(9g), —OC(O)R^(9h)and —N(R¹¹)R^(9i);

R³, R⁴ and R⁵ may also, at each occurrence when used herein,independently represent H;

R⁴, R⁵ and R⁸ may also, at each occurrence when used herein,independently represent aryl;

R² represents H, aryl, Het⁴ or lower alkyl, which latter group isoptionally substituted and/or terminated by one or more substituentsselected from lower alkyl (which latter group is optionally substitutedand/or terminated by one or more substituents selected from —OH andhalo), aryl, Het⁵, halo, —CN, —NO₂, —OR^(9a), —C(O)R^(9b), —C(O)OR^(9c),—C(O)N(R^(9d))R^(9e), —S(O)₂R^(10a), —S(O)₂N(R^(9f))R^(9g), —OC(O)R^(9h)or —N(R¹¹)R^(9i);

R¹¹ represents, at each occurrence when used herein, H, aryl, loweralkyl (which alkyl group is optionally substituted by one or moresubstituents selected from aryl and halo), —C(O)R^(9j),—C(O)N(R^(9k))R^(9m) or —S(O)₂R^(10b);

R^(9a) to R^(9m) independently represent, at each occurrence when usedherein, H, aryl or lower alkyl (which alkyl group is optionallysubstituted by one or more substituents selected from aryl and halo);

R^(10a) and R^(10b) represent, at each occurrence when used herein, arylor lower alkyl (which alkyl group is optionally substituted by one ormore substituents selected from aryl and halo);

Het¹ represents an optionally substituted four- to twelve-memberedheterocyclic group, which group contains at least one nitrogen atom (viawhich atom the Het¹ group is attached to the rest of the molecule) and,optionally, one or more further heteroatoms selected from nitrogen,oxygen and/or sulfur;

Het² to Het⁵ independently represent optionally substituted four- totwelve-membered heterocyclic groups, which groups contain one or moreheteroatoms selected from nitrogen, oxygen and/or sulfur;

each aryl group is optionally substituted with one or more substituentsselected from halo, lower alkyl (which latter group is optionallysubstituted by one or more substituents selected from —CN, —NO₂,—OR^(9a), —C(O)R^(9b), —C(O)OR^(9c), —C(O)N(R^(9d))R^(9e),—S(O)₂N(R^(9f))R^(9g), —S(O)_(n)R^(10a), —OC(O)R^(9h) and—N(R¹¹)R^(9i)), —CN, —NO₂, —OR^(9a), —C(O)R^(9b), —C(O)OR^(9c),C(O)N(R^(9d))R^(9e), —S(O)_(n)R^(10a), —S(O)₂N(R^(9f))R^(9g),—OC(O)R^(9h) and —N(R¹¹)R^(9i); Het¹, Het², Het³, Het⁴ and Het⁵ are eachoptionally substituted with one or more substituents selected from loweralkyl (which alkyl group may itself be optionally substituted and/orterminated by one or more substituents selected from lower alkyl, aryl,Het², halo, —CN, —NO₂, —OR^(9a), —C(O)R^(9b), —C(O)OR^(9c),—C(O)N(R^(9d))R^(9e), —S(O)_(n)R^(10a), —S(O)₂N(R^(9f))R^(9g),—OC(O)R^(9h) and —N(R¹¹)R^(9i)), aryl, Het², halo, —CN, —NO₂, —OR^(9a),—C(O)R^(9b), —C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), —S(O)₂R^(10a),—S(O)₂N(R^(9f))R^(9g), —OC(O)R^(9h) and —N(R¹¹)R^(9i); and

n represents, at each occurrence when used herein, 0, 1 or 2;

or a pharmaceutically, or a veterinarily, acceptable derivative thereof;

provided that when the compound is a compound of formula IB in which:

X represents CH;

R¹ represents H;

R³ represents C₁₋₈ alkyl; and

Het¹ represents a 5- or 6-membered saturated heterocyclic ring, whichring is optionally substituted (via a free ring N-atom) by C₁₋₆ alkyl(which latter group is optionally substituted by —OH); then R² does notrepresent:

(a) C₃₋₁₁ alkyl, which C₃₋₁₁ alkyl group is substituted by one of thefollowing:

(i) in the C-1 position (relative to the purinone N-atom), by—C(O)R^(9b) (wherein R^(9b) represents H or C₁₋₄ alkyl) or C₁₋₁₁ alkyl;

(ii) in the C-2 position (relative to the purinone N-atom) by one groupselected from —OR^(9a) (wherein R^(9a) represents H, C₁₋₆ alkyl orbenzyl), —OC(O)R^(9h) (wherein R^(9h) represents H, C₁₋₆ alkyl orphenyl) and —N(R¹¹)R^(9i) (wherein R^(9i) represents H or C₁₋₆ alkyl andR¹¹ represents H, C₁₋₆ alkyl, —C(O)R^(9j) (in which R^(9j) represents H,C₁₋₆ alkyl or phenyl) or —S(O)₂R^(10b) (in which R^(10b) represents C₁₋₄alkyl or phenyl)) and (optionally), at the same C-2 position, by afurther C₁₋₄ alkyl group;

and which C₃₋₁₁ alkyl group is optionally substituted:

(I) in the C-2 to C-11 positions (relative to the purinone N-atom), byphenyl (optionally substituted by halo, —CN, —NO₂, C₁₋₆ alkyl or—S(O)₂N(R^(9f))R^(9g), in which latter group R^(9f) and R^(9g)independently represent H, phenyl or lower alkyl); and/or

(II) in the C-1 position (relative to the purinone N-atom), by C₁₋₃alkyl;

(b) C₃₋₉ alkyl substituted in the C-2 to C-9 positions (relative to thepurinone N-atom) by —N(R¹¹)R^(9i) (wherein R¹¹ and R^(9i) eachindependently represent H or C₁₋₅ alkyl optionally substituted byphenyl, which latter group is substituted by —S(O)₂N(R^(9f))R^(9g) (inwhich R^(9f) and R^(9g) independently represent H, phenyl or loweralkyl)) and optionally substituted in the C-1 position (relative to thepurinone N-atom) by:

(i) C₁₋₅ alkyl (which alkyl group is optionally substituted by —OH);and/or

(ii) C₁₋₃ alkyl; or

(c) C₁₋₄ alkyl or C₁₀₋₁₆ n-alkyl;

wherein, in the above proviso, unless otherwise indicated, alkyl, phenyland benzyl groups are unsubstituted,

which compounds are referred to together hereinafter as “the compoundsof the invention”.

The term “aryl”, when used herein, includes six- to ten-memberedcarbocyclic aromatic groups, such as phenyl and naphthyl. Unlessotherwise specified, each aryl group identified herein is optionallysubstituted with one or more substituents selected from halo, loweralkyl (which latter group is optionally substituted by one or moresubstituents selected from —CN, —NO₂, —OR^(9a), —C(O)R^(9b),—C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), —S(O)₂N(R^(9f))R^(9g),S(O)_(n)R^(10a), —OC(O)R^(9h) and —N(R¹¹)R^(9i)), —CN, —NO₂, —OR^(9a),—C(O)R^(9b), —C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), S(O)_(n)R^(10a),—S(O)₂N(R^(9f))R^(9g), —OC(O)R^(9h), and —N(R¹¹)R^(9h) (in which n,R^(9a) to R^(9i) and R^(10a) are as hereinbefore defined). When aryl issubstituted by a group containing one or more further aryl substituents,then such further aryl substituents may not be substituted by groupscontaining aryl substituents.

Het (Het¹, Het², Het³, Het⁴, Het⁵) groups may be fully saturated, partlyunsaturated, wholly aromatic, partly aromatic and/or bicyclic incharacter. Unless otherwise specified, each Het (Het¹, Het², Het³, Het⁴,Het⁵) group identified herein is optionally substituted with one or moresubstituents selected from lower alkyl (which alkyl group may itself beoptionally substituted and/or terminated as defined below in respect ofR¹²), aryl, Het², halo, —CN, —NO₂, —OR^(9a), —C(O)R^(9b), —C(O)OR^(9c),—C(O)N(R^(9d))R^(9e), —S(O)_(n)R^(10a), —S(O)₂N(R^(9f))R^(9g),—OC(O)R^(9h), or —N(R¹¹)R^(9i) (in which n, R^(9a) to R^(9i), R^(10a),aryl and Het² are as hereinbefore defined). Het (Het¹, Het², Het³, Het⁴,Het⁵) groups that may be mentioned include groups such as optionallysubstituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl,pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridyl, quinolinyl,isoquinolinyl, piperidinyl, pyrazolyl, imidazopyridinyl and piperazinyl,e.g. 4-R¹²-piperazinyl, wherein R¹² represents H or lower alkyl, whichlatter group is optionally substituted and/or terminated by one or moresubstituents selected from lower alkyl, aryl, Het², halo, —CN, —NO₂,—OR^(9a), C(O)R^(9b), —C(O)OR^(9c), —C(O)N(R^(9d))R^(9e),—S(O)_(n)R^(10a), —S(O)₂N(R^(9f))R^(9g), —OC(O)R^(9h) or —N(R¹¹)R^(9i)(in which n, R^(9a) to R^(9i), R^(10a), aryl and Het² are ashereinbefore defined). When a Het (Het¹, Het², Het³, Het⁴, Het⁵) groupis substituted either directly by a further Het² group or by asubstituent containing a further Het² group, then such further Het²groups may not be substituted either directly by a Het group or by asubstituent containing a further Het² group.

The point of attachment of any Het², Het³, Het⁴ and Het⁵ groups may bevia any atom in the ring system including (where appropriate) aheteroatom. Het (Het¹, Het², Het³, Het⁴, Het⁵) groups may also bepresent in the N- or S-oxidised form.

The term “lower alkyl”, when used herein, includes C₁₋₂ alkyl, such asC₁₋₉ alkyl (e.g. C₁₋₆ alkyl). Unless otherwise specified, alkyl groupsmay, when there is a sufficient number of carbon atoms, be linear orbranched, be saturated or unsaturated, be cyclic, acyclic or partcyclic/acyclic, be interrupted by oxygen, and/or be substituted by oneor more halo atoms.

As defined herein, the term “halo” includes fluoro, chloro, bromo andiodo.

For the avoidance of doubt, each R⁴, R⁵, R⁸, R^(9a) to R^(9m), R^(10a),R^(10b), R¹¹ and Het² group referred to herein is independent of otherR⁴, R⁵, R⁸, R^(9a) to R^(9m), R^(10a), R^(10b), R¹¹ and Het² groups,respectively. For example, when R² and R⁴ both represent alkylsubstituted by —OR^(9a), the two individual —OR^(9a) substituents areindependent of one another, and are not necessarily identical (thoughthis possibility is not excluded).

The pharmaceutically or veterinarily acceptable salts of the compoundsof the invention which contain a basic centre are, for example,non-toxic acid addition salts formed with inorganic acids such ashydrochloric, hydrobromic, hydroiodic, sulphuric and phosphoric acid,with carboxylic acids or with organo-sulphonic acids. Examples includethe HCl, HBr, HI, sulphate or bisulphate, nitrate, phosphate or hydrogenphosphate, acetate, benzoate, succinate, saccarate, fumarate, maleate,lactate, citrate, tartrate, gluconate, camsylate, methanesulphonate,ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoatesalts. Compounds of the invention can also provide pharmaceutically orveterinarily acceptable metal salts, in particular non-toxic alkali andalkaline earth metal salts, with bases. Examples include the sodium,potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.For a review on suitable pharmaceutical salts see Berge et al, J. Pharm,Sci., 66, 1-19, 1977. Pharmaceutically acceptable derivatives alsoinclude C₁₋₄ alkyl ammonium salts.

The pharmaceutically acceptable solvates of the compounds of theinvention include the hydrates thereof.

Also included within the scope of the compound and various salts of theinvention are polymorphs thereof.

A compound of the formula (I) contains one or more asymmetric carbonatoms and therefore exists in two or more stereoisomeric forms. Where acompound of the formula (I) contains an alkenyl or alkenylene group, cis(E) and trans (Z) isomerism may also occur. The present inventionincludes the individual stereoisomers of the compounds of the formula(I) and, where appropriate, the individual tautomeric forms thereof,together with mixtures thereof. Separation of diastereoisomers or cisand trans isomers may be achieved by conventional techniques, e.g. byfractional crystallisation, chromatography or H.P.L.C. of astereoisomeric mixture of a compound of the formula (I) or a suitablesalt or derivative thereof. An individual enantiomer of a compound ofthe formula (I) may also be prepared from a corresponding optically pureintermediate or by resolution, such as by H.P.L.C. of the correspondingracemate using a suitable chiral support or by fractionalcrystallisation of the diastereoisomeric salts formed by reaction of thecorresponding racemate with a suitable optically active acid or base, asappropriate.

All stereoisomers are included within the scope of the invention.

Abbreviations are listed at the end of this specification.

According to a further aspect of the invention there is providedcompounds of formulae IA and IB as hereinbefore defined (but without theproviso), provided that, in the case of compounds of formula IB (or, ina still further aspect of the invention, in the case of compounds offormulae IA and/or IB), at least one of the following applies:

(1) R¹ represents —CN, —C(O)N(R⁴)R⁵, —C(O)R⁴, —C(O)OR⁴, —N(R⁴)R⁶, —OR⁷,aryl, Het² or lower alkyl (which alkyl group is optionally interruptedby one or more of —O—, —S— or —N(R⁴)— and/or substituted and/orterminated by one or more substituents selected from halo, —CN, —NO₂,lower alkyl, —C(O)N(R⁴)R⁵, —C(O)R⁴, —C(O)OR⁴, —N(R⁴)R⁶, —OR⁷,—S(O)_(n)R⁴ or —S(O)_(n)N(R⁴)R⁵, aryl and Het²);

(2) R² represents H, aryl, Het⁴, C₁₋₂ alkyl (which latter group issubstituted by one or more substituents selected from aryl, —OR^(9a),—C(O)R^(9b), —OC(O)R^(9h) and —N(R¹¹)R^(9i)) or lower alkyl, whichlatter group is substituted and/or terminated by:

(i) one or more substituents selected from halo, —CN, —NO₂, Het⁵,—OR^(9a), —C(O)R^(9b) (wherein R^(9a) and R^(9b) represent aryl or loweralkyl (which alkyl group is substituted by one or more halo atoms))—C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), —S(O)₂R^(10a), —S(O)₂N(R^(9f))R^(9g)and —N(R¹¹)R^(9i) (wherein R¹¹ represents aryl or —C(O)N(R^(9k))R^(9m));and/or

(ii) more than one substituent selected from —OR^(9a) (wherein R^(9a)represents aryl or lower alkyl (which alkyl group is optionallysubstituted by one or more substituents selected from aryl and halo)),—C(O)R^(9b), —OC(O)R^(9h) and —N(R¹¹)R^(9i);

(3) R³ represents H or lower alkyl, which alkyl group is substitutedand/or terminated by one or more substituents selected from aryl, Het³,halo, —CN, —NO₂, —OR^(9a), —C(O)R^(9b), —C(O)OR^(9c),—C(O)N(R^(9d))R^(9e), —S(O)₂R^(10a), —S(O)₂N(R^(9f))R^(9g), —OC(O)R^(9h)and —N(R¹¹)R^(9i);

(4) Het¹ represents:

(i) a 4- or 7- to 12-membered optionally substituted heterocyclic groupas hereinbefore defined;

(ii) a 5- or 6-membered fully saturated heterocyclic group ashereinbefore defined, which group is not substituted by C₁₋₆ alkyloptionally substituted by —OH; or

(iii) a 5- or 6-membered optionally substituted, partly unsaturated oraromatic, heterocyclic group as hereinbefore defined; and/or

(5) X represents N, wherein, unless otherwise specified, substituents n,R⁴, R⁵, R⁶, R⁷, R^(9a) to R^(9m), R^(10a), R¹¹, Het², Het⁴ and Het⁵ havemeanings given in the first aspect of the invention providedhereinbefore.

Preferred compounds of the invention include those wherein:

R¹ represents H, —CN, —C(O)N(R⁴)R⁵, —C(O)R⁴, —C(O)OR⁴, —N(R⁴)R⁶, —OR⁷,aryl, Het² or C₁₋₆ alkyl (which alkyl group is optionally substituted orterminated by one or more substituents selected from halo, —CN, —NO₂,lower alkyl, —C(O)N(R⁴)R⁵, —C(O)R⁴, —C(O)OR⁴, —N(R⁴)R⁵, —OR⁷,S(O)_(n)R⁴, —S(O)_(n)N(R⁴)R⁵, aryl and Het²);

R⁶ represents R⁵, —S(O)₂R⁸ or —C(O)R⁴;

R⁷represents R⁴;

n represents 0 or 2;

R³, R⁴, R⁵ and R⁸ independently represent lower alkyl, which alkyl groupis optionally substituted and/or terminated by one or more substituentsselected from aryl, Het³, halo, —CN, —NO₂, —OR⁹a or —N(R¹¹)R^(9i);

R³, R⁴ and R⁵ may also independently represent H;

R⁴, R⁵ and R⁸ may also independently represent aryl;

R² represents H, aryl, Het⁴ or lower alkyl, which latter group isoptionally substituted and/or terminated by one or more substituentsselected from halo, —CN, —NO₂, aryl, Het⁵, —OR^(9a), —C(O)R^(9b),—C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), —S(O)_(n)R^(10a),—S(O)₂N(R^(9f))R^(9g) or —N(R¹¹)R^(9i);

R¹¹ represents, at each occurrence, H, C₁₋₆ alkyl or —C(O)R^(9j);

R^(9a) to R^(9j) independently represent, at each occurrence, H or C₁₋₆alkyl;

R^(10a) represents C₁₋₆ alkyl;

Het¹ represents an optionally substituted (as hereinbefore defined)four- to seven-membered heterocyclic group, which group contains atleast one nitrogen atom (via which atom the Het¹ group is attached tothe rest of the molecule) and, optionally, one or more furtherheteroatoms selected from nitrogen and oxygen;

Het² to Het⁵ independently represent optionally substituted (ashereinbefore defined) four- to ten-membered heterocyclic groups, whichgroups contain between one and four heteroatoms selected from nitrogen,oxygen and/or sulfur.

More preferred compounds of the invention include those wherein:

R¹ represents H, —C(O)N(R⁴)R⁵, —C(O)OR⁴, —N(R⁴)R⁶, —OR⁷, optionallysubstituted phenyl, Het² or C₁₋₃ alkyl (which alkyl group is optionallysubstituted or terminated by one or more substituents selected fromhalo, C₁₋₃ alkyl, —C(O)N(R⁴)R⁵, —C(O)OR⁴, —N(R⁴)R⁶, —OR⁷, optionallysubstituted phenyl, and Het²);

R⁶ represents H, C₁₋₄ alkyl, —S(O)₂—(C₁₋₄ alkyl) or —C(O)—(C₁₋₄ alkyl);

R⁷ represents H, or C₁₋₄ alkyl;

R³, R⁴, R⁵ independently represent H or C₁₋₆ alkyl, which alkyl group isoptionally substituted and/or terminated by one or more substituentsselected from phenyl, Het³, halo, —OR^(9a) or —N(R¹¹)R^(9i);

R⁴ and R⁵ may also independently represent optionally substitutedphenyl;

R² represents H, optionally substituted phenyl, Het⁴ or C₁₋₆ alkyl,which latter group is optionally substituted and/or terminated by one ormore substituents selected from halo, —CN, —NO₂, phenyl, Het⁵, —OR^(9a),—C(O)R^(9b), —C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), —S(O)₂—(C₁₋₄ alkyl),—S(O)₂N(R^(9f))R^(9g), or —N(R¹¹)R^(9i);

R¹¹ represents, at each occurrence, H or C₁₋₄ alkyl;

R^(9a) to R^(9i) independently represent, at each occurrence, H or C₁₋₄alkyl;

Het¹ represents a fully saturated, optionally substituted (ashereinbefore defined) four- to six-membered heterocyclic group, whichgroup contains at least one nitrogen atom (via which atom the Het¹ groupis attached to the rest of the molecule) and, optionally, one or morefurther nitrogen atoms;

Het² to Het⁵ independently represent four- to ten-membered heterocyclicgroups, which groups contain between one and four heteroatoms selectedfrom nitrogen, oxygen and/or sulfur, and which groups are optionallysubstituted by one or more substituents selected from phenyl, Het²,halo, —CN, —NO₂, lower alkyl (which alkyl group is optionallysubstituted by one or more substituents selected from halo, phenyl,—OR^(9a) and —N(R¹¹)R^(9i)) —OR^(9a), —C(O)R^(9b), —C(O)OR^(9c),—C(O)N(R^(9d))R^(9e), —S(O)₂N(R^(9f))R^(9g) and —N(R¹¹)R^(9i).

Still further preferred compounds of the invention include thosewherein:

R¹ represents H, phenyl, Het² or C₁₋₂ alkyl (which alkyl group isoptionally substituted or terminated by one or more substituentsselected from halo, C₁₋₂ alkyl, phenyl (which phenyl group is optionallysubstituted by one or more substituents selected from halo, —CN, —NO₂,—OR^(9a), —C(O)R^(9b), —C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), and—N(R¹¹)R^(9i)), and Het²);

R³ represents C₁₋₄ alkyl, which alkyl group is optionally substitutedand/or terminated by one or more substituents selected from phenyl,Het³, halo, —OR^(9a) or —N(R¹¹)R^(9i);

R² represents H, phenyl (which phenyl group is optionally substituted byone or more substituents selected from halo, —CN, —NO₂, —OR^(9a)—C(O)R^(9b), —C(O)OR^(9c), —C(O)N(R^(9d))R^(9e) and —N(R¹¹)R^(9i)) orC₁₋₄ alkyl (which alkyl group is optionally substituted and/orterminated by one or more substituents selected from halo, —CN, —NO₂,phenyl, Het⁵, —OR^(9a) or —N(R¹¹)R^(9i));

Het¹ represents a fully saturated six-membered heterocyclic group, whichgroup contains at least one nitrogen atom (via which atom the Het¹ groupis attached to the rest of the molecule) and, optionally, one or morefurther nitrogen atoms, and which group is optionally substituted by oneor more substituents selected from aryl, Het², halo, C₁₋₄ alkyl,—C(O)R^(9b), and —C(O)OR^(9c);

Het² represents a six-membered optionally aromatic heterocyclic group,which group contains at least one nitrogen atom and optionally one ortwo further heteroatoms selected from nitrogen, oxygen and/or sulfur,and which group is optionally substituted by one or more substituentsselected from halo, —CN, C₁₋₄ alkyl, —C(O)R^(9b), —C(O)OR^(9c) and—N(H)R¹¹; R^(9a) to R^(9e), R^(9i) and R¹¹ represent, at eachoccurrence, H or C₁₋₂ alkyl.

Particularly preferred compounds of the invention include those wherein:

R¹ represents H, —CH₃, -benzyl or -pyridyl;

R² represents H, phenyl (which phenyl group is optionally substituted byone or more substituents selected from —NO₂ and —NH₂) or C₁₋₃ alkyl;

R³ represents C₂₋₄ alkyl;

Het¹ represents piperazin-1-yl, optionally substituted in the 4-positionby C₁₋₂ alkyl or pyridyl.

Preferred compounds of the invention include the compounds of theExamples described hereinafter.

Thus, according to a further aspect of the invention, there is provideda compound of formula I which, irrespective of any of the foregoingdefinitions and/or provisos, is:

2-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-9H-purin-6-one;

8-benzyl-2-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)phenyl]-9-n-propyl-purin-6-one;

2-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-9-(4-nitrophenyl)-purin-6-one;

9-(4-aminophenyl)-2-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxy-phenyl]purin-6-one;

2-[5-(4-methylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-8-(pyridin-3-yl)-9H-purin-6-one;

2-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-8-methyl-9-n-propylpurin-6-one;

8-benzyl-2-[2-n-butoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-9-n-propylpurin-6-one;

2-(2-n-propoxy-5-[4-{pyridin-2-yl}piperazin-1-ylsulfonyl]phenyl)-9H-purin-6-one;

2-(2-n-propoxy-5-[4-{pyridin-2-yl}piperazin-1-ylsulfonyl]phenyl)-9-n-propylpurin-6-one;

2-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-7-n-propylpurin-6-one;

2-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-7-(4-nitrophenyl)-purin-6-one;or

7-(4-aminophenyl)-2-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxy-phenyl]purin-6-one;

which compounds may also be termed “compounds of the invention”.

Especially preferred compounds of the invention include those wherein:

R¹ represents H, —CH₃, -benzyl or -pyridyl;

R² represents H, phenyl (which phenyl group is substituted (e.g. inposition 4 relative to the point of attachment to the nitrogen atom) byone or more substituents selected from —NO₂ and —NH₂) or propyl;

R³ represents C₂₋₄ alkyl;

Het¹ represents piperazin-1-yl, optionally substituted in the 4-positionby C₁₋₂ alkyl.

The compounds of the invention may exhibit tautomerism. All tautomericforms of the compounds of formulae IA and IB, and mixtures thereof, areincluded within the scope of the invention.

The compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism. Diastereoisomers may be separated using conventionaltechniques e.g. by fractional crystallisation or chromatography. Thevarious stereoisomers may be isolated by separation of a racemic orother mixture of the compounds using conventional techniques e.g.fractional crystallisation or HPLC. The desired optical isomers may beprepared by reaction of the appropriate optically active startingmaterials under conditions which will not cause racemisation orepimerisation. Alternatively, the desired optical isomers may beprepared by resolution, either by HPLC of the racemate using a suitablechiral support or, where appropriate, by fractional crystallisation ofthe diastereoisomeric salts formed by reaction of the racemate with asuitable optically active acid or base. All stereoisomers are includedwithin the scope of the invention.

Also included within the scope of the invention are radiolabelledderivatives of compounds of formulae IA and IB which are suitable forbiological studies.

Preparation

According to a further aspect of the invention there is providedprocesses for the preparation of compounds of the invention, asillustrated below.

The following processes are illustrative of the general syntheticprocedures which may be adopted in order to obtain the compounds of theinvention:

1. Compounds of formulae IA and IB may be prepared by cyclisation ofcorresponding compounds of formulae IIA and IIB, respectively,

wherein R¹, R², R³, Het¹ and X are as hereinbefore defined.

This cyclisation may be accomplished under basic, neutral or acidicconditions using known methods for pyrimidinone ring formation.Preferably, the cyclisation is performed under basic conditions using analkali metal salt of an alcohol or amine, such as potassiumtert-butoxide or potassium bis(trimethylsilyl) amide, in the presence ofa suitable solvent (e.g. an alcohol), for example at elevated (e.g.reflux) temperature (or, if a sealed vessel is employed, at above refluxtemperature). The skilled person will appreciate that, when an alcoholis selected as solvent, an appropriate alcohol of formula R³OH, or asterically hindered alcohol, e.g. 3-methyl pentan-3-ol, may be used ifit is intended to mitigate alkoxide exchange at either the 2-position ofthe pyridin-3-yl, or the phenyl, substituent.

Compounds of formulae IIA and IIB may be prepared by reaction ofcorresponding compounds of formulae IIIA and IIIB, respectively,

wherein R¹ and R² are as hereinbefore defined, with a compound offormula IV,

or a suitable carboxylic acid derivative thereof (e.g. an acid halide oranhydride), wherein R³, Het¹ and X are as hereinbefore defined.

This coupling reaction may be achieved by conventional amide bondforming techniques which are well known to those skilled in the art. Forexample, an acid halide (e.g. chloride) derivative of a compound offormula IV may be reacted with a compound of formula IIIA or IIIB, atbetween −10° C. and room temperature, in the presence of an appropriatebase (e.g. triethylamine, pyridine or, especially, sodium hydride) andoptionally in the presence of a suitable catalyst (e.g.4-(dimethylamino)-pyridine) and/or a suitable solvent (e.g.dichloromethane, THF or N,N-dimethylformamide).

A variety of other amino acid coupling methodologies may be used tocouple a compound of formula IIIA or IIIB with a compound of formula IV.For example, the acid of formula IV or a suitable salt thereof (e.g.sodium salt) may be activated with an appropriate activating reagent(e.g. a carbodiimide, such as 1,3-dicyclohexylcarbodiimide or1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride; ahalotrisamino-phosphonium salt such as bromotripyrrolidinophosphoniumhexafluoro-phosphate or benzotriazol-1-yloxytrispyrrolidinophosphoniumhexafluoro-phosphate; or a suitable pyridinium salt such as2-chloro-1-methyl pyridinium chloride), optionally in the presence of1-hydroxybenzotriazole hydrate and/or a catalyst such as4-(dimethylamino)pyridine. The coupling reaction may be conducted in asuitable solvent such as dichloromethane, N,N-dimethylformamide ortetrahydrofuran, in the presence of a suitable base (e.g. sodium hydrideand, optionally, 4-methylmorpholine or N-ethyldiisopropylamine), atbetween −10° C. and +60° C. Preferably, from about 1 to 2 molecular eqs.of the activating reagent and from 1 to 3 molecular eqs. of any basepresent may be employed.

Alternatively, the carboxylic acid function of IV may be activated, atbetween room and reflux temperature, using an excess of a reagent suchas 1,1′-carbonyldiimidazole in an appropriate solvent, e.g. ethylacetate, dichloromethane or butan-2-one, followed by reaction of theintermediate imidazolide, at between room and reflux temperature, with acompound of formula IIIA or IIIB.

Compounds of formula IV may be prepared by standard techniques known tothose skilled in the art from a corresponding halophenyl or3-halopyridyl precursor, via hydrolysis (e.g. under basic conditions) ofan intermediate alkoxycarbonyl compound, which latter compound may beobtained by reaction of the halophenyl or 3-halopyridyl compound withcarbon monoxide and a lower alkyl (e.g. C₁₋₄) alcohol in the presence ofa suitable catalyst system (e.g.tetrakis(triphenylphosphine)palladium(0)).

2. Compounds of formulae IA and IB may alternatively be prepared byreaction of corresponding compounds of formulae VA and VB, respectively,

wherein L¹ is a leaving group (e.g. halo) and R¹, R², R³ and X are ashereinbefore defined, with a compound of formula VI,

Het¹—H  VI

wherein Het¹ is as hereinbefore defined, provided that the essentialnitrogen atom of the heterocycle is attached to the H-atom.

This reaction is typically performed at between −10° C. and roomtemperature in the presence of an appropriate solvent (e.g. a C₁₋₃alcohol, ethyl acetate or dichloromethane), an excess of the compound offormula VI and, optionally, another suitable base (e.g. triethylamine orN-ethyldiisopropylamine).

Compounds of formula VA and VB, in which X represents N, may be preparedfrom corresponding compounds of formulae VIIA and VIIB, respectively,

wherein R¹, R² and R³ are as hereinbefore defined, for example usingmethods known to those skilled in the art for converting an amino groupto an SO₂L¹ group, in which L¹ is as hereinbefore defined. For example,compounds of formulae VA and VB in which L¹ is chloro may be prepared byreacting a corresponding compound of formula VIIA or VIIB, at betweenabout −25 and about 0° C., with about a 1.5 to 2-fold excess of sodiumnitrite in a mixture of concentrated hydrochloric acid and glacialacetic acid, followed by treatment, at between −30° C. and roomtemperature, with excess liquid sulfur dioxide and a solution of about athree-fold excess of cupric chloride in aqueous acetic acid.

Compounds of formulae VIIA and VIIB may be prepared by cyclisation ofcorresponding compounds of formulae VIIIA and VIIIB, respectively,

wherein R¹, R² and R³ are as hereinbefore defined. This cyclisation maybe carried out using similar techniques to those described hereinbeforefor the preparation of compounds of formulae IA and IB, but it ispreferably base-mediated.

Compounds of formulae VIIIA and VIIIB may be prepared by the reductionof corresponding compounds of formulae IXA and IXB, respectively,

wherein R¹, R² and R³ are as hereinbefore defined, for example byconventional techniques, such as catalytic hydrogenation. Typically, thehydrogenation may be achieved at between 40 and 50° C. using a Raney®nickel catalyst in a suitable solvent (e.g. ethanol) at a hydrogenpressure of between 150 kPa and 500 kPa, especially 345 kPa.

Compounds of formulae IXA and IXB may be prepared by reaction ofcorresponding compounds of formulae IIIA and IIIB, as hereinbeforedefined, with a compound of formula X,

or a suitable carboxylic acid derivative (e.g. an acid halide) thereof,wherein R³ is as hereinbefore defined, for example using analogous amidebond forming techniques to those previously described for the synthesisof compounds of formulae IIA and IIB.

Compounds of formulae VIIA and VIIB may alternatively be prepared byreduction of corresponding compounds of formulae XIA and XIB,respectively:

wherein R¹, R² and R³ are as hereinbefore defined. This reduction may beperformed under a variety of reaction conditions, for example bycatalytic hydrogenation (e.g. using 10% Pd/C in an alcohol, such asethanol, at 415 kPa H₂ pressure and room temperature) or by transitionmetal catalysed reduction (e.g. at around room temperature in thepresence of iron powder (e.g. 7 eq.) in acetic acid, or TiCl₃ (e.g. 9eq.) in acetic acid).

Compounds of formulae XIA and XIB may be prepared by cyclisation ofcorresponding compounds of formulae IXA and IXB, respectively, forexample under conditions described hereinbefore for the synthesis ofcompounds of formulae IA and IB.

Compounds of formulae XIA and XIB in which R¹ represents lower alkyl(which alkyl group is branched and unsaturated at the carbon atom thatis attached to the rest of the molecule), —N(R⁴)R⁵, —CN, aryl or Het²(which Het² group is either aromatic, or is unsaturated at the carbonatom that is attached to the rest of the molecule) may alternatively beprepared by reaction of corresponding compounds of formulae XIVA orXIVB, respectively,

wherein R², R³ and L¹ are as hereinbefore defined, with a compound offormula XV,

R^(1a)M  XV

wherein R^(1a) represents lower alkyl (which alkyl group is branched andunsaturated at the carbon atom that is attached to the rest of themolecule), —N(R⁴)R⁵, —CN, aryl or Het² (which Het² group is eitheraromatic, or is unsaturated at the carbon atom that is attached to M), Mrepresents H or an optionally substituted metal or boron group, whichgroup is suitable for cross-coupling reactions (such as atrialkylstannane (e.g. tri-n-butylstannane), a dialkylborane (e.g.diethylborane), a dialkoxyborane, a dihydroxyborane, lithium, ahalomagnesium, a halozinc, copper, or a halomercury), and R⁴ and R⁵ areas hereinbefore defined, for example in the presence of an appropriatecatalyst system (e.g. a palladium or nickel catalyst).

The cross-coupling reaction is preferably carried out in the presence ofa base (e.g. potassium carbonate, cesium fluoride or triethylamine),preferably in excess. Those skilled in the art will appreciate that thetype of catalyst that is employed will depend on factors such as thenature of the M group, and the substrate that is employed etc.

Suitable coupling conditions include so-called “Suzuki” conditions (e.g.1.2 eq. of boronic acid, 2 eq. of K₂CO₃ and 0.1 eq. of Pd(PPh₃)₄,refluxing in an approximately 4:1 mixture of dioxane:water, or 2.5 to 3eq. of CsF, 0.05 to 0.1 eq. of Pd₂(dba)₃ and 0.01 to 0.04 eq ofP(o-tol)₃, refluxing in DME); or so-called “Stille” conditions (1.5 eq.of stannane, 10 eq. of LiCl, 0.15 eq. of Cul, and 0.1 eq. of Pd(PPh₃)₄,refluxing in dioxane, or 5 eq. of stannane, 3.6 eq. of Et₃N, Pd₂(dba)and P(o-tol)₃, refluxing in MeCN).

In a further typical procedure, a compound of formula XV may be used, inwhich M is halozinc. Such a compound may be prepared by reaction of acompound R^(1a)-halo, where halo and R^(2a) are as hereinbefore defined,with an alkyllithium (e.g. n-butyllithium) at between −78° C. and roomtemperature in a suitable solvent (e.g. THF), and the resultant solutionis then treated with Zn(II) chloride (solution in ether). The resultingmixture is then treated with a compound of formula XIVA or XIVB in thepresence of a palladium catalyst (e.g. tetrakis(triphenyl)phosphinepalladium(0)) in a suitable solvent (e.g. THF). The reaction may becarried out at between room and reflux temperature.

Compounds of formulae XIVA and XIVB in which L¹ represents halo may beprepared by halogenation of corresponding compounds of formulae XIA andXIB, respectively, in which R¹ represents H, under conditions known tothose skilled in the art. Such conditions include, for example, in thecase where L¹ represents bromo, reaction at between 10 and 50° C. withbromine in the presence of a suitable solvent (e.g. water ordichloromethane).

Compounds of formulae VA and VB, in which X is N, may alternatively beprepared from corresponding compounds of formulae XVIA and XVIB,respectively,

wherein R¹, R² and R³ are as hereinbefore defined, for example by way ofknown reactions that will result in conversion of a thiol to an —SO₂L¹group. For example, for compounds of formulae VA and VB in which L¹represents halo, the reaction may be carried out at between −10° C. andreflux temperature in the presence of a suitable oxidising agent (e.g.potassium nitrate), an appropriate halogenating agent (e.g. thionylchloride) and a suitable solvent (e.g. acetonitrile).

Compounds of formulae XVIA and XVIB may be prepared by reaction ofcorresponding compounds of formulae XVIIA and XVIIB, respectively,

wherein R¹, R², R³ and L¹ are as hereinbefore defined (and L¹ ispreferably iodo), with a suitable sulfur-delivering reagent. Forexample, the reaction may be carried out at between room and refluxtemperature in the presence of thiourea, an appropriate couplingcatalyst (e.g. dichlorobis(triethylphosphine)nickel(II) in combinationwith a reducing agent such as sodium cyanoborohydride) and a suitablesolvent (e.g. N,N-dimethylformamide), followed by hydrolysis in thepresence of a base such as calcium oxide.

Compounds of formulae XVIIA and XVIIB may be prepared by cyclisation ofcorresponding compounds of formulae XVIIIA and XVIIIB, respectively,

wherein R¹, R², R³ and L¹ are as hereinbefore defined. This cyclisationmay be carried out using similar techniques to those describedhereinbefore for the preparation of compounds of formulae IA and IB, butit is preferably base-mediated.

Compounds of formulae XVIIIA and XVIIIB may be prepared by reaction ofcorresponding compounds of formulae IIIA and IIIB, respectively, ashereinbefore defined, with a compound of formula XIX,

or a suitable carboxylic acid derivative (e.g. an acid halide) thereof,wherein R³ is as hereinbefore defined, for example using analogous amidebond forming techniques to those previously described for the synthesisof compounds of formulae IIA and IIB.

Compounds of formulae VA and VB, in which X is CH, may be prepared fromcorresponding compounds of formulae XXA and XXB, respectively,

wherein R¹, R² and R³ are as hereinbefore defined, for example usingconventional methods for the introduction of a —SO₂L¹ group into anaromatic ring system, such as reaction of a compound of formula XXA orXXB, optionally in the presence of an appropriate solvent (e.g.dichloromethane), with a compound of formula L¹SO₃H and (optionally) acompound of formula SO(L¹)₂. When L¹ is chloro, reaction may take placeat between 0° C. and room temperature in the presence of an excess ofchlorosulfonic acid (optionally in conjunction with an excess of thionylchloride), and optionally in an appropriate organic solvent (e.g.dichloromethane).

Compounds of formulae XXA and XXB are available using known techniques.For example, compounds of formulae XXA and XXB, in which R² representsaryl, Het⁴ or optionally substituted lower alkyl, may be prepared byreaction of corresponding compounds of formulae XXA and XXB,respectively, in which R² represents H, with a compound of formula XXI,

R^(2a)—L²  XXI

wherein R^(2a) represents aryl, Het⁴ or lower alkyl (which latter groupis optionally substituted as defined hereinbefore in respect of R² incompounds of formulae IA and IB), and L² represents a leaving group suchas halo, alkane sulfonate, perfluoroalkane sulfonate or arene sulfonate,for example using methods which are known to those skilled in the art.Preferably, the leaving group is halo (preferably chloro, bromo or iodo)and the reaction is performed at between −70 and 140° C. in the presenceof a suitable base (e.g. cesium carbonate, potassium hydroxide or sodiumhydride), an appropriate solvent (e.g. N,N-dimethylformamide, DMSO orTHF), and optionally in the presence of sodium iodide or potassiumiodide. Preferably the alkylation is conducted at between roomtemperature and 80° C.

Those skilled in the art will appreciate that, in compounds of formulaXXI in which R^(2a) represents Het⁴ or aryl, the R^(2a) group may needto be activated by the presence of one or more electron-withdrawinggroups for reaction with compounds of formulae XXA and XXB (in which R²represents H) to take place. Suitable electron-withdrawing groups forthis purpose include nitro, formyl, acyl and alkoxycarbonyl. Such groupsmay be introduced and/or removed from the relevant aryl or Het⁴ groupusing methods and under conditions that are known to those skilled inthe art.

Compounds of formulae XXA and XXB in which R² represents optionallysubstituted lower alkyl may be obtained by reaction of compounds offormulae XXA and XXB, respectively, in which R² represents H, with acompound of formula XXII,

R^(2b)—OH  XXII

wherein R^(2b) represents lower alkyl (which alkyl group is optionallysubstituted as defined hereinbefore in respect of R² in compounds offormulae IA and IB), for example under Mitsunobu-type conditions knownto those skilled in the art.

Compounds of formulae XXA and XXB may alternatively be prepared bycyclisation of corresponding compounds of formulae XXIIIA and XXIIIB,respectively,

wherein R¹, R² and R³ are as hereinbefore defined, for example underanalogous conditions to those described previously for the synthesis ofcompounds of formulae IA and IB.

Compounds of formulae XXIIIA and XXIIIB may be prepared by reaction ofcorresponding compounds of formulae IIIA or IIIB, respectively, ashereinbefore defined, with a compound of formula XXIV,

or a suitable carboxylic acid derivative (e.g. an acid halide) thereof,wherein R³ is as hereinbefore defined, for example using analogous amidebond forming techniques to those previously described for the synthesisof compounds of formulae IIA and IIB.

Compounds of formulae XXIIIA and XXIIIB may alternatively be prepared byreaction of corresponding compounds of formulae XXIVA or XXIVB,respectively,

wherein R¹³ represents a lower (e.g. C₁₋₆) alkyl group and R¹ and R² areas hereinbefore defined, with a compound of formula XXIV, ashereinbefore defined, followed by conversion of the —C(O)OR¹³ group ofthe resultant amide into a —C(O)NH₂ group, using conventional techniquesknown to those skilled in the art. In a particular embodiment, theconversion of the —C(O)OR¹³ group to a primary amide function andcyclisation of the resultant compound of formula XXIIIA or XXIIIB (togive a compound of formula XXA or XXB, respectively), may beaccomplished in a one-pot procedure. Preferably, this one-pot procedureis accomplished with a saturated methanolic ammonia solution, in thepresence of base (e.g. potassium t-butoxide), under pressure, atelevated temperatures, especially at 100° C.

Compounds of formulae XXA and XXB in which R² represents H may beprepared by reaction of a corresponding compound of formula XXV,

wherein R³ is as hereinbefore defined, with a compound of formula XXVI,

R¹—CHO  XXVI

wherein R¹ is as hereinbefore defined, for example at between room andreflux temperature, optionally in the presence of a suitable mildoxidant (e.g. sodium metabisulfite), and optionally in an appropriateorganic solvent (e.g. N,N-dimethyl acetamide).

Compounds of formulae XXA and XXB in which R² represents H mayalternatively be prepared by reaction of a corresponding compound offormula XXV, as hereinbefore defined, with a compound of formula XXVII,

R¹—C(O)OH  XXVII

or a suitable carboxylic acid derivative thereof (e.g. an acid halide oran ortho ester), for example at between room and reflux temperature,optionally in the presence of a suitable solvent (e.g. N,N-dimethylformamide) and/or an appropriate base.

3. Compounds of formulae IA and IB, in which R² represents aryl, Het⁴ oroptionally substituted lower alkyl, may be prepared by reaction ofcorresponding compounds of formulae IA and IB in which R² represents Hwith a compound of formula XXI, as hereinbefore defined, for example asdescribed hereinbefore for preparation of compounds of formulae XXA andXXB.

4. Compounds of formulae IA and IB, in which R² represents optionallysubstituted lower alkyl, may be prepared by reaction of correspondingcompounds of formulae IA and IB in which R² represents H with a compoundof formula XXII, as hereinbefore defined, for example as describedhereinbefore for preparation of compounds of formulae XXA and XXB.

Compounds of formulae IIIA, IIIB, VI, X, XV, XIX, XXI, XXII, XXIV,XXIVA. XXIVB, XXV, XXVI, XXVII and derivatives thereof, when notcommercially available or not subsequently described, may be obtainedeither by analogy with the processes described hereinbefore, or byconventional synthetic procedures, in accordance with standardtechniques, from readily available starting materials using appropriatereagents and reaction conditions. For example, compounds of formula XXVmay be prepared by, or by analogy with, methods described in EP 352 960.

Substituents on aryl and Het (Het¹, Het², Het³, Het⁴, Het⁵) groups inthe above-mentioned compounds may be introduced, removed andinterconverted, using techniques which are well known to those skilledin the art. For example, compounds of formulae IA and IB as describedhereinbefore, in which R² represents an aminophenyl group, may beprepared by reducing corresponding compounds of formula IA or IB, inwhich R² represents a nitrophenyl group. The reaction may be performedusing methods which are well known to those skilled in the art, forexample under reduction conditions described hereinbefore.

The skilled person will also appreciate that various standardsubstituent or functional group interconversions and transformationswithin certain compounds of formulae IA and IB will provide othercompounds of formulae IA and IB. For example, alkoxide exchange at the2-position of the 5-phenyl and the pyridin-3-yl substituents. Moreover,certain compounds of formulae IA and IB, for example those in which Het¹represents a 4-R¹²-piperazinyl group, in which R¹² does not represent H,may be prepared directly from the corresponding piperazine analogues inwhich R¹² represents H, using standard procedures (e.g. alkylation).

The compounds of the invention may be isolated from their reactionmixtures using conventional techniques.

It will be appreciated by those skilled in the art that, in the courseof carrying out the processes described above, the functional groups ofintermediate compounds may need to be protected by protecting groups.

Functional groups which it is desirable to protect include hydroxy,amino and carboxylic acid. Suitable protecting groups for hydroxyinclude trialkylsilyl and diarylalkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl and alkylcarbonyl groups (e.g. methyl- andethylcarbonyl). Suitable protecting groups for amino includetert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl.Suitable protecting groups for carboxylic acid include C₁₋₆ alkyl orbenzyl esters.

The protection and deprotection of functional groups may take placebefore or after any of the reaction steps described hereinbefore.

Protecting groups may be removed in accordance with techniques which arewell known to those skilled in the art.

The use of protecting groups is fully described in “Protective Groups inOrganic Chemistry”, edited by J W F McOmie, Plenum Press (1973), and“Protective Groups in Organic Synthesis”, 2^(nd) edition, T W Greene & PG M Wutz, Wiley-Interscience (1991).

Persons skilled in the art will also appreciate that, in order to obtaincompounds of formula I in an alternative, and, on some occasions, moreconvenient, manner, the individual process steps mentioned hereinbeforemay be performed in a different order, and/or the individual reactionsmay be performed at a different stage in the overall route (i.e.substituents may be added to and/or chemical transformations performedupon, different intermediates to those mentioned hereinbefore inconjunction with a particular reaction). This will depend inter alia onfactors such as the nature of other functional groups present in aparticular substrate, the availability of key intermediates and theprotecting group strategy (if any) to be adopted. Clearly, the type ofchemistry involved will influence the choice of reagent that is used inthe said synthetic steps, the need, and type, of protecting groups thatare employed, and the sequence for accomplishing the synthesis.

Pharmaceutically acceptable acid addition salts of the compounds offormulae IA and IB which contain a basic centre may be prepared in aconventional manner. For example, a solution of the free base may betreated with the appropriate acid, either neat or in a suitable solvent,and the resulting salt may then be isolated either by filtration or byevaporation under vacuum of the reaction solvent. Pharmaceuticallyacceptable base addition salts can be obtained in an analogous manner bytreating a solution of a compound of formula IA or IB with theappropriate base. Both types of salt may be formed or interconvertedusing ion-exchange resin techniques.

The present invention also includes all suitable isotopic variations ofa compound of the formula (I) or a pharmaceutically acceptable saltthereof. An isotopic variation of a compound of the formula (I) or apharmaceutically acceptable salt thereof is defined as one in which atleast one atom is replaced by an atom having the same atomic number butan atomic mass different from the atomic mass usually found in nature.Examples of isotopes that can be incorporated into compounds of theformula (I) and pharmaceutically acceptable salts thereof includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur,fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P,³⁵S, ¹⁸F and ³⁶Cl, respectively. Certain isotopic variations of thecompounds of the formula (I) and pharmaceutically acceptable saltsthereof, for example, those in which a radioactive isotope such as 3H or14C is incorporated, are useful in drug and/or substrate tissuedistribution studies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with isotopes such as deuterium,i.e., ²H, may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example, increased in vivo half-life orreduced dosage requirements and hence may be preferred in somecircumstances. Isotopic variations of the compounds of formula (I) andpharmaceutically acceptable salts thereof of this invention cangenerally be prepared by conventional procedures such as by theillustrative methods or by the preparations described in the Examplesand Preparations hereafter using appropriate isotopic variations ofsuitable reagents.

It will be appreciated by those skilled in the art that certainprotected derivatives of compounds of formulae IA or IB, which may bemade prior to a final deprotection stage, may not possesspharmacological activity as such, but may, in certain instances, beadministered orally or parenterally and thereafter metabolised in thebody to form compounds of the invention which are pharmacologicallyactive. Such derivatives may therefore be described as “prodrugs”.Further, certain compounds of formulae IA and IB may act as prodrugs ofother compounds of formulae IA and IB, respectively.

All protected derivatives, and prodrugs, of compounds of formulae IA andIB are included within the scope of the invention.

The present invention additionally comprises the combination of a cGMPPDE₅ inhibitor, in particular a compound of the general formula (I)with:

(a) one or more naturally occurring or synthetic prostaglandins oresters thereof. Suitable prostaglandins for use herein include compoundssuch as alprostadil, prostaglandin E₁,prostaglandin E₀, 13,14-dihydroprosta glandin E₁, prostaglandin E₂, eprostinol, naturalsynthetic and semi-synthetic prostaglandins and derivatives thereofincluding those described in U.S. Pat. No. 6,037,346 issued on Mar. 14,2000 and incorporated herein by reference, PGE₀, PGE₁, PGA₁, PGB₁, PGF₁,α, 19-hydroxy PGA₁, 19-hydroxy-PGB₁, PGE₂, PGB₂, 19-hydroxy-PGA₂,19-hydroxy-PGB₂, PGE₃α, carboprost tromethamine dinoprost, tromethamine,dinoprostone, lipo prost, gemeprost, metenoprost, sulprostune, tiaprostand moxisylate; and/or

(b) one or more α-adrenergic receptor antagonist compounds also known asα-adrenoceptors or α-receptors or α-blockers. Suitable compounds for useherein include: the α-adrenergic receptors as described in PCTapplication WO99/30697 published on Jun. 14, 1998, the disclosures ofwhich relating to α-adrenergic receptors are incorporated herein byreference and include, selective α₁-adrenoceptors or α₂-adrenoceptorsand non-selective adrenoceptors, suitable α₁-adrenoceptors include:phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramin,naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan,efaraxan, yohimbine, rauwolfa alkaloids, Recordati 15/2739, SNAP 1069,SNAP 5089, RS17053, SL 89.0591, doxazosin, terazosin, abanoquil andprazosin; α₂-blockers from U.S. Pat. No. 6,037,346 [Mar. 14, 2000]dibenamine, tolazoline, trimazosin and dibenamine; α-adrenergicreceptors as described in U.S. Pat. Nos.: 4,188,390; 4,026,894;3,511,836; 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063;3,381,009; 4,252,721 and 2,599,000 each of which is incorporated hereinby reference; α₂-Adrenoceptors include: clonidine, papaverine,papaverine hydrochloride, optionally in the presence of a cariotonicagent such as pirxamine; and/or

(c) one or more NO-donor (NO-agonist) compounds. Suitable NO-donorcompounds for use herein include organic nitrates, such as mono-di ortri-nitrates or organic nitrate esters including glyceryl brinitrate(also known as nitroglycerin), isosorbide 5-mononitrate, isosorbidedinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodiumnitroprusside (SNP), 3-morpholinosydnonimine molsidomine,S-nitroso-N-acetyl penicilliamine (SNAP) S-nitroso-N-glutathione(SNO-GLU), N-hydroxy —L-arginine, amylnitrate, linsidomine, linsidominechlorohydrate, (SIN-1) S-nitroso —N-cysteine, diazeniumdiolates,(NONOates), 1,5-pentanedinitrate, L-maxisylyte arginene,ginseng, zizphi fructus, molsidomine, Re-2047, nitrosylated derivativessuch as NMI-678-11 and NMI-937 as described in published PCT applicationWO 0012075; and/or

(d) one or more potassium channel openers. Suitable potassium channelopeners for use herein include nicorandil, cromokalim, levcromakalim,lemakalim, pinacidil, cliazoxide, minoxidil, charybdotoxin, glyburide,4-amini pyridine, BaCl₂; and/or

(e) one or more dopaminergic agents. Suitable dopaminergic compounds foruse herein include D₂-agonists such as, pramipexol; apomorphine; and/or

(f) one or more vasodilator agents. Suitable vasodilator agents for useherein include nimodepine, pinacidil, cyclandelate, isoxsuprine,chloroprumazine, halo peridol, Rec 15/2739, trazodone, pentoxifylline;and/or

(g) one or more thromboxane A2 agonists; and/or

(h) one or more CNS active agents; and/or

(i) one or more ergot alkoloids; Suitable ergot alkaloids are describedin U.S. Pat. No. 6,037,346 issued on Mar. 14, 2000 and includeacetergamine, brazergoline, bromerguride, cianergoline, delorgotrile,disulergine, ergonovine maleate, ergotamine tartrate, etisulergine,lergotrile, lysergide, mesulergine, metergoline, metergotamine,nicergoline, pergolide, propisergide, proterguride, terguride; and/or

(k) one or more compounds which modulate the action of atrial natrureticfactor (also known as atrial naturetic peptide), such as inhibitors orneutral endopeptidase; and/or

(l) one or more compounds which inhibit angiotensin-converting enzymesuch as enapril, and combined inhibitors of angiotensin-convertingenzyme and neutral endopeptidase such as omapatrilat; and/or

(m) one or more angiotensin receptor antagonists such as losartan;and/or

(n) one or more substrates for NO-synthase, such as L-arginine; and/or

(o) one or more calcium channel blockers such as amlodipine; and/or

(p) one or more antagonists of endothelin receptors and inhibitors orendothelin-converting enzyme; and/or

(q) one or more cholesterol lowering agents such as statins andfibrates; and/or

(r) one or more antiplatelet and antithrombotic agents, e.g. tPA, uPA,warfarin, hirudin and other thrombin inhibitors, heparin, thromboplastinactivating factor inhibitors; and/or

(s) one or more insulin sensitising agents such as rezulin andhypoglycaemic agents such as glipizide; and/or

(t) L-DOPA or carbidopa; and/or

(u) one or more acetylcholinesterase inhibitors such as donezipil;and/or

(v) one or more steroidal or non-steroidal anti-inflammatory agents.

Medical Use

The compounds of the invention are useful because they possesspharmacological activity in animals, especially mammals, includinghumans. They are therefore indicated as pharmaceuticals, as well as foruse as animal medicaments.

According to a further aspect of the invention there is provided thecompounds of the invention for use as pharmaceuticals, and for use asanimal medicaments.

In particular, compounds of the invention have been found to be potentand selective inhibitors of cGMP PDEs, such as cGMP PDE5, for example asdemonstrated in the tests described below, and are thus useful in thetreatment of medical conditions in humans, and in animals, in which cGMPPDEs, such as cGMP PDE5, are indicated, and in which inhibition of cGMPPDEs, such as cGMP PDE5, is desirable.

By the term “treatment”, we include both therapeutic (curative),palliative or prophylactic treatment.

Thus, according to a further aspect of the invention there is providedthe use of the compounds of the invention in the manufacture of amedicament for the treatment of a medical condition in which a cGMP PDE(e.g. cGMP PDE5) is indicated. There is further provided the use of thecompounds of the invention in the manufacture of a medicament for thetreatment of a medical condition in which inhibition of a cGMP PDE (e.g.cGMP PDE5) is desirable.

The compounds of the invention are thus expected to be useful for thecurative, palliative or prophylactic treatment of mammalian sexualdisorders. In particular, the compounds are of value in the treatment ofmammalian sexual dysfunctions such as male erectile dysfunction (MED),impotence, female sexual dysfunction (FSD), clitoral dysfunction, femalehypoactive sexual desire disorder, female sexual arousal disorder,female sexual pain disorder or female sexual orgasmic dysfunction (FSOD)as well as sexual dysfunction due to spinal cord injury but, clearly,will be useful also for treating other medical conditions for which apotent and selective cGMP PDE5 inhibitor is indicated. Such conditionsinclude premature labour, dysmenorrhoea, benign prostatic hyperplasia(BPH), bladder outlet obstruction, incontinence, stable, unstable andvariant (Prinzmetal) angina, hypertension, pulmonary hypertension,chronic obstructive pulmonary disease, coronary artery disease,congestive heart failure, atherosclerosis, conditions of reduced bloodvessel patency, e.g. post-percutaneous transluminal coronary angioplasty(post-PTCA), peripheral vascular disease, stroke, nitrate inducedtolerance, bronchitis, allergic asthma, chronic asthma, allergicrhinitis, glaucoma and diseases characterised by disorders of gutmotility, e.g. irritable bowel syndrome (IBS).

Further medical conditions for which a potent and selective cGMP PDE5inhibitor is indicated, and for which treatment with compounds of thepresent invention may be useful include pre-eclampsia, Kawasaki'ssyndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy,peripheral diabetic neuropathy, Alzheimer's disease, acute respiratoryfailure, psoriasis, skin necrosis, cancer, metastasis, baldness,nutcracker oesophagus, anal fissure, haemorrhoids and hypoxicvasoconstriction.

Particularly preferred conditions include MED and FSD.

Thus the invention provides a method of treating or preventing a medicalcondition for which a cGMP PDE5 inhibitor is indicated, in an animal(e.g. a mammal, including a human being), which comprises administeringa therapeutically effective amount of a compound of the invention to amammal in need of such treatment.

Pharmaceutical Preparations

The compounds of the invention will normally be administered orally orby any parenteral route, in the form of pharmaceutical preparationscomprising the active ingredient, optionally in the form of a non-toxicorganic, or inorganic, acid, or base, addition salt, in apharmaceutically acceptable dosage form. Depending upon the disorder andpatient to be treated, as well as the route of administration, thecompositions may be administered at varying doses.

The compounds of the invention may also be combined with any other drugsuseful in the inhibition of cGMP-PDEs, such as cGMP-PDE5.

The compounds of formulae (IA) or (1B), their pharmaceuticallyacceptable salts, and pharmaceutically acceptable solvates of eitherentity can be administered alone but, in human therapy will generally beadministered in admixture with a suitable pharmaceutical excipientdiluent or carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice.

For example, the compounds of formulae (IA) or (1B) or salts or solvatesthereof can be administered orally, buccally or sublingually in the formof tablets, capsules (including soft gel capsules), ovules, elixirs,solutions or suspensions, which may contain flavouring or colouringagents, for immediate-, delayed-, modified-, sustained-,controlled-release or pulsatile delivery applications. The compounds ofthe invention may also be administered via intracavernosal injection.The compounds of the invention may also be administered via fastdispersing or fast dissolving dosages forms.

Such tablets may contain excipients such as microcrystalline cellulose,lactose, sodium citrate, calcium carbonate, dibasic calcium phosphateand glycine, disintegrants such as starch (preferably corn, potato ortapioca starch), sodium starch glycollate, croscarmellose sodium andcertain complex silicates, and granulation binders such aspolyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC),hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, stearic acid, glycerylbehenate and talc may be included.

Solid compositions of a similar type may also be employed as fillers ingelatin capsules. Preferred excipients in this regard include lactose,starch, a cellulose, milk sugar or high molecular weight polyethyleneglycols. For aqueous suspensions and/or elixirs, the compounds of theformula (IA) or (IB) may be combined with various sweetening orflavouring agents, colouring matter or dyes, with emulsifying and/orsuspending agents and with diluents such as water, ethanol, propyleneglycol and glycerin, and combinations thereof.

Modified release and pulsatile release dosage forms may containexcipients such as those detailed for immediate release dosage formstogether with additional excipients that act as release rate modifiers,these being coated on and/or included in the body of the device. Releaserate modifiers include, but are not exclusively limited to,hydroxypropylmethyl cellulose, methyl cellulose, sodiumcarboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethyleneoxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer,hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetatephthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acidcopolymer and mixtures thereof. Modified release and pulsatile releasedosage forms may contain one or a combination of release rate modifyingexcipients. Release rate modifying excipients maybe present both withinthe dosage form i.e. within the matrix, and/or on the dosage form i.e.upon the surface or coating.

Fast dispersing or dissolving dosage formulations (FDDFs) may containthe following ingredients: aspartame, acesulfame potassium, citric acid,croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate,ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesiumstearate, mannitol, methyl methacrylate, mint flavouring, polyethyleneglycol, fumed silica, silicon dioxide, sodium starch glycolate, sodiumstearyl fumarate, sorbitol, xylitol.

The compounds of the invention can also be administered parenterally,for example, intracavernosally, intravenously, intra-arterially,intraperitoneally, intrathecally, intraventricularly, intraurethrallyintrasternally, intracranially, intramuscularly or subcutaneously, orthey may be administered by infusion techniques. For such parenteraladministration they are best used in the form of a sterile aqueoussolution which may contain other substances, for example, enough saltsor glucose to make the solution isotonic with blood. The aqueoussolutions should be suitably buffered (preferably to a pH of from 3 to9), if necessary. The preparation of suitable parenteral formulationsunder sterile conditions is readily accomplished by standardpharmaceutical techniques well-known to those skilled in the art.

For oral and parenteral administration to human patients, the dailydosage level of the compounds of formula (IA) or (1B) or salts orsolvates thereof will usually be from 10 to 500 mg (in single or divideddoses).

Thus, for example, tablets or capsules of the compounds of formulae (IA)or (IB) or salts or solvates thereof may contain from 5 mg to 250 mg ofactive compound for administration singly or two or more at a time, asappropriate. The physician in any event will determine the actual dosagewhich will be most suitable for any individual patient and it will varywith the age, weight and response of the particular patient. The abovedosages are exemplary of the average case. There can, of course, beindividual instances where higher or lower dosage ranges are merited andsuch are within the scope of this invention. The skilled person willalso appreciate that, in the treatment of certain conditions (includingMED and FSD), compounds of the invention may be taken as a single doseon an “as required” basis (i.e. as needed or desired).

Example Tablet Formulation

In general a tablet formulation could typically contain between about0.01 mg and 500 mg of a compound according to the present invention (ora salt thereof) whilst tablet fill weights may range from 50 mg to 1000mg. An example formulation for a 10 mg tablet is illustrated:

Ingredient % w/w Compound of Example 7 10.000* Lactose 64.125 Starch21.375 Croscarmellose Sodium  3.000 Magnesium Stearate  1.500 *Thisquantity is typically adjusted in accordance with drug activity.

The compounds of the invention can also be administered intranasally orby)inhalation and are conveniently delivered in the form of a dry powderinhaler or an aerosol spray presentation from a pressurised container,pump, spray or nebuliser with the use of a suitable propellant, e.g.dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, a hydrofluoroalkane such as1,1,1,2-tetrafluoroethane (HFA 134A [trade mark] or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbondioxide or other suitable gas. In the case of a pressurised aerosol, thedosage unit may be determined by providing a valve to deliver a meteredamount. The pressurised container, pump, spray or nebuliser may containa solution or suspension of the active compound, e.g. using a mixture ofethanol and the propellant as the solvent, which may additionallycontain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges(made, for example, from gelatin) for use in an inhaler or insufflatormay be formulated to contain a powder mix of a compound of the formula(IA) or (IB) and a suitable powder base such as lactose or starch.

Aerosol or dry powder formulations are preferably arranged so that eachmetered dose or “puff” contains from 1 to 50 mg of a compound of theformula (IA) or (IB) for delivery to the patient. The overall daily dosewith an aerosol will be in the range of from 1 to 50 mg which may beadministered in a single dose or, more usually, in divided dosesthroughout the day.

The compounds of the invention may also be formulated for delivery viaan atomiser. Formulations for atomiser devices may contain the followingingredients as solubilisers, emulsifiers or suspending agents: water,ethanol, glycerol, propylene glycol, low molecular weight polyethyleneglycols, sodium chloride, fluorocarbons, polyethylene glycol ethers,sorbitan trioleate, oleic acid.

Alternatively, the compounds of the formulae (IA) or (IB) or salts orsolvates thereof can be administered in the form of a suppository orpessary, or they may be applied topically in the form of a gel,hydrogel, lotion, solution, cream, ointment or dusting powder. Thecompounds of the formulae (IA) and (IB) or salts or solvates thereof mayalso be dermally administered. The compounds of the formulae (IA) or(IB) or salts or solvates thereof may also be transdermallyadministered, for example, by the use of a skin patch. They may also beadministered by the ocular, pulmonary or rectal routes.

For ophthalmic use, the compounds can be formulated as micronisedsuspensions in isotonic, pH adjusted, sterile saline, or, preferably, assolutions in isotonic, pH adjusted, sterile saline, optionally incombination with a preservative such as a benzylalkonium chloride.Alternatively, they may be formulated in an ointment such as petrolatum.

For application topically to the skin, the compounds of the formulae(IA) or (IB) or salts or solvates thereof can be formulated as asuitable ointment containing the active compound suspended or dissolvedin, for example, a mixture with one or more of the following: mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, they can be formulated as a suitable lotion or cream,suspended or dissolved in, for example, a mixture of one or more of thefollowing: mineral oil, sorbitan monostearate, a polyethylene glycol,liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

The compounds of the formula (IA) or (IB) may also be used incombination with a cyclodextrin. Cyclodextrins are known to forminclusion and non-inclusion complexes with drug molecules. Formation ofa drug-cyclodextrin complex may modify the solubility, dissolution rate,bioavailability and/or stability property of a drug molecule.Drug-cyclodextrin complexes are generally useful for most dosage formsand administration routes. As an alternative to direct complexation withthe drug the cyclodextrin may be used as an auxiliary additive, e.g. asa carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrinsare most commonly used and suitable examples are described inWO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

Generally, in humans, oral administration of the compounds of theinvention is the preferred route, being the most convenient and, forexample in MED, avoiding the well-known disadvantages associated withintracavernosal (i.c.) administration. A preferred oral dosing regimenin MED for a typical man is from 25 to 250 mg of compound when required.In circumstances where the recipient suffers from a swallowing disorderor from impairment of drug absorption after oral administration, thedrug may be administered parenterally, sublingually or buccally.

For veterinary use, a compound of formula (IA) or (IB), or aveterinarily acceptable salt thereof, or a veterinarily acceptablesolvate or pro-drug thereof, is administered as a suitably acceptableformulation in accordance with normal veterinary practice and theveterinary surgeon will determine the dosing regimen and route ofadministration which will be most appropriate for a particular animal.

Thus, according to a further aspect of the invention there is provided apharmaceutical formulation including a compound of the invention inadmixture with a pharmaceutically or veterinarily acceptable adjuvant,diluent or carrier.

In addition to the fact that compounds of the invention inhibit cyclicguanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs) and inparticular, are potent and selective inhibitors of cGMP PDE5, compoundsof the invention may also have the advantage that they may be moreefficacious than, be less toxic than, have a broader range of activitythan, be more potent than, produce fewer side effects than, be moreeasily absorbed than, or they may have other useful pharmacologicalproperties over, compounds known in the prior art.

The biological activities of the compounds of the present invention weredetermined by the following test methods.

Biological Tests

Phosphodiesterase (PDE) Inhibitory Activity

In vitro PDE inhibitory activities against cyclic guanosine3′,5′-monophosphate (cGMP) and cyclic adenosine 3′,5′-monophosphate(cAMP) phosphodiesterases were determined by measurement of their IC₅₀values (the concentration of compound required for 50% inhibition ofenzyme activity).

The required PDE enzymes were isolated from a variety of sources,including human corpus cavernosum, human and rabbit platelets, humancardiac ventricle, human skeletal muscle and bovine retina, essentiallyby the method of W. J. Thompson and M. M. Appleman (Biochem., 1971, 10,311). In particular, the cGMP-specific PDE (PDE5) and the cGMP-inhibitedcAMP PDE (PDE3) were obtained from human corpus cavernosum tissue, humanplatelets or rabbit platelets; the cGMP-stimulated PDE (PDE2) wasobtained from human corpus cavernosum; the calcium/calmodulin(Ca/CAM)-dependent PDE (PDE1) from human cardiac ventricle; thecAMP-specific PDE (PDE4) from human skeletal muscle; and thephotoreceptor PDE (PDE6) from bovine retina. Phosphodiesterases 7-11were generated from full length human recombinant clones transfectedinto SF9 cells.

Assays were performed either using a modification of the “batch” methodof W. J. Thompson et al. (Biochem., 1979, 18, 5228) or using ascintillation proximity assay for the direct detection of AMP/GMP usinga modification of the protocol described by Amersham plc under productcode TRKQ7090/7100. In summary, the effect of PDE inhibitors wasinvestigated by assaying a fixed amount of enzyme in the presence ofvarying inhibitor concentrations and low substrate, (cGMP or cAMP in a3:1 ratio unlabelled to [³H]-labeled at a conc ˜⅓ K_(m)) such thatIC₅₀≅K_(i). The final assay volume was made up to 100 μl with assaybuffer [20 mM Tris-HCl pH 7.4, 5 mM MgCl₂, 1 mg/ml bovine serumalbumin]. Reactions were initiated with enzyme, incubated for 30-60 minat 30° C. to give <30% substrate turnover and terminated with 50 μlyttrium silicate SPA beads (containing 3 mM of the respective unlabelledcyclic nucleotide for PDEs 9 and 11). Plates were re-sealed and shakenfor 20 min, after which the beads were allowed to settle for 30 min inthe dark and then counted on a TopCount plate reader (Packard, Meriden,Conn.) Radioactivity units were converted to % activity of anuninhibited control (100%), plotted against inhibitor concentration andinhibitor IC₅₀ values obtained using the ‘Fit Curve’ Microsoft Excelextension. Results from these tests show that the compounds of thepresent invention are potent and selective inhibitors of cGMP-specificPDE5.

Functional Activity

This was assessed in vitro by determining the capacity of a compound ofthe invention to enhance sodium nitroprusside-induced relaxation ofpre-contracted rabbit corpus cavernosum tissue strips, as described byS. A. Ballard et al. (Brit. J. Pharmacol., 1996, 118 (suppl.), abstract153P).

In Vivo Activity

Compounds were screened in anaesthetised dogs to determine theircapacity, after i.v. administration, to enhance the pressure rises inthe corpora cavernosa of the penis induced by intracavernosal injectionof sodium nitroprusside, using a method based on that described byTrigo-Rocha et al. (Neurourol. and Urodyn., 1994, 13, 71).

Safety Profile

Compounds of the invention may be tested at varying i.v and p.o. dosesin animals such as mouse and dog, observing for any untoward effects.

EXAMPLES AND PREPARATIONS

The invention is illustrated by the following Preparations and Examples.

¹H nuclear magnetic resonance (NMR) spectra were recorded using either aVarian Unity 300 or a Varian Inova 400 spectrometer and were in allcases consistent with the proposed structures. Characteristic chemicalshifts (δ) are given in parts-per-million downfield fromtetramethylsilane.

Mass spectra (m/z) were recorded using a low resolution massspectrometer.

Room temperature includes 20 to 25° C.

Synthesis of Intermediates

Preparation 1 5-Amino-2-methyl-1-n-propylimidazole-4-carboxamide

A mixture of 2-amino-2-cyanoacetamide (prepared as described in WO94/00453; 3.6 g, 36.4 mmol) and ethyl acetimidate hydrochloride (4.50 g,36.4 mmol) in acetonitrile (85 mL) was stirred at 50° C. for an hour,then cooled to 0° C., and stirred for a further hour. The reactionmixture was filtered, and n-propylamine (3.02 mL, 36.4 mmol) added. Thesolution was stirred at room temperature for an hour, and left to standfor a further 16 hours. The resulting precipitate was filtered, washedwith acetonitrile, then dichloromethane and dried under vacuum to affordthe title compound as a solid (3.0 g, 45%).

δ(DMSO-d₆, 300 MHz): 0.85 (3H, t), 1.58 (2H, m), 2.17 (3H, s), 3.68 (2H,t), 5.66 (2H, s), 6.50 (2H, br s).

Preparation 2 5-Amino-2-benzyl-1-n-propylimidazole-4-carboxamide

A solution of 2-amino-2-cyanoacetamide (prepared as described in WO94/00453; 250 mg, 2.5 mmol) in acetonitrile (6 mL) was added to ethyl2-phenylethanimidoate hydrochloride (prepared as described in J. Med.Chem. 38 (18), 3676 (1995); 500 mg, 2.5 mmol), and the suspensionstirred at room temperature for an hour, then cooled in an ice-bath. Theresulting precipitate was filtered off, n-propylamine (160 μL, 2.5 mmol)added to the filtrate and the solution stirred at room temperature for72 hours. The reaction mixture was concentrated under reduced pressure,and the residue purified by column chromatography on silica gel usingdichloromethane:methanol (95:5) as eluant to afford the title compoundas a tan coloured solid (136 mg, 21%).

δ(DMSO-d₆, 400 MHz): 0.68 (3H, t), 1.24 (2H, m), 3.55 (2H, t), 3.92 (2H,s), 5.70 (2H, s), 7.14-7.28 (5H, m).

Preparation 32-Benzyl-5-(2-ethoxybenzamido)-1-n-propylimidazole-4-carboxamide

(i) Oxalyl chloride (0.28 mL, 3.21 mmol) was added to an ice-cooledsolution of 2-ethoxybenzoic acid (130 mg, 0.78 mmol) in dichloromethane(5 mL), followed by N,N-dimethylformamide (1 drop), and the reactionstirred at room temperature for 2 hours. The solution was concentratedunder reduced pressure, azeotroped with dichloromethane and the residueredissolved in tetrahydrofuran (5 mL).

(ii) Sodium hydride (48 mg, 60% dispersion in mineral oil, 1.2 mmol) wasadded to a solution of5-amino-2-benzyl-1-n-propylimidazole-4-carboxamide (Preparation 2; 200mg, 0.77 mmol) in tetrahydrofuran (5 mL), and the mixture stirred for 3hours at room temperature. The prepared solution of acid chloride (from(i) above) was then added and the reaction stirred at room temperaturefor 2 days. The mixture was concentrated under reduced pressure, theresidue partitioned between dichloromethane and water, and the layersseparated. The organic phase was dried (MgSO₄) and evaporated underreduced pressure. The crude product was purified by columnchromatography on silica gel twice, using an elution gradient ofdichloromethane: methanol (100:0 to 95:5) to afford the title compound(114 mg, 36%).

δ(CDCl₃, 300 MHz): 0.74 (3H, t), 1.42-1.60 (5H, m), 3.88 (2H, t), 4.12(2H, s), 4.36 (2H, q), 5.30 (1H, br s), 6.86 (1H, br s), 7.03 (2H, m),7.20-7.37 (5H, m), 7.50 (1H, m), 8.20 (1H, m), 10.42 (1H, s).

LRMS: m/z 407 (M+1)⁺.

Preparation 4 2-n-Butoxypyridine-3-carboxylic Acid

Sodium (3.0 g, 130 mmol) was added to n-butanol (100 mL), and themixture warmed to 80° C. until a solution was obtained, and then2-chloro-nicotinic acid (10.0 g, 63.4 mmol) added, and the reactionheated under reflux for 4 hours. The cooled mixture (which solidified oncooling) was crushed and then partitioned between ethyl acetate andaqueous hydrochloric acid (sufficient to achieve pH 4), and the layersseparated. The organic phase was washed with brine, and evaporated underreduced pressure. The residue was redissolved in ethyl acetate, dried(MgSO₄) and re-evaporated to give the title compound as a solid (11.9 g,96%).

LRMS: m/z 196 (M+1)⁺.

Preparation 5 2-n-Butoxy-5-iodopyridine-3-carboxylic acid

N-Iodosuccinimide (6.0 g, 26.7 mmol) was added to a solution of2-n-butoxypyridine-3-carboxylic acid (Preparation 4; 3.46 g, 17.7 mmol)in trifluoroacetic acid (28 mL) and trifluoroacetic anhydride (7 mL) andthe reaction heated under reflux in the absence of light, for 3 hours.The cooled reaction mixture was concentrated under reduced pressure andthe residue dissolved in ethyl acetate. This solution was washedsequentially with water (2×), aqueous sodium thiosulfate solution,aqueous sodium citrate solution, 2 N hydrochloric acid, and brine, thendried (MgSO₄) and evaporated under reduced pressure. The solid wastriturated with pentane, filtered, washed with additional pentane anddried, to give the title compound as a white solid (3.86 g, 68%).

Anal. Found: C, 37.10; H, 3.70; N, 4.21. C₁₀H₁₂INO₃ requires C, 37.40;H, 3.76; N, 4.36%.

δ(CDCl₃, 400 MHz): 1.00 (3H, t), 1.50 (2H, m), 1.85 (2H, m), 4.59 (2H,t), 8.55 (1H, s), 8.70 (1H, s).

Preparation 6 Pyridine-2-amino-5-sulfonic Acid

2-Aminopyridine (80 g, 0.85 mol) was added portion-wise over 30 minutesto oleum (320 g) and the resulting solution heated at 140° C. for 4hours. On cooling, the reaction was poured onto ice (200 g) and themixture stirred in an ice/salt bath for a further 2 hours. The resultingsuspension was filtered, the solid washed with ice water (200 mL) andcold IMS (200 mL) and dried under suction to afford the title compoundas a solid (111.3 g, 75%).

LRMS: m/z 175 (M+1)⁺.

Preparation 7 Pyridine-2-amino-3-bromo-5-sulfonic Acid

Bromine (99 g, 0.62 mol) was added dropwise over an hour, to a hotsolution of pyridine-2-amino-5-sulfonic acid (Preparation 6; 108 g, 0.62mol) in water (600 mL) so as to maintain a steady reflux. Once theaddition was complete the reaction was cooled and the resulting mixturefiltered. The solid was washed with water and dried under suction toafford the title compound (53.4 g, 34%).

δ(DMSO-d₆, 300 MHz): 8.08 (1H, s), 8.14 (1H, s).

LRMS: m/z 253 (M)⁺.

Preparation 8 Pyridine-3-bromo-2-chloro-5-sulfonyl Chloride

A solution of sodium nitrite (7.6 g, 110.0 mmol) in water (30 mL) wasadded dropwise to an ice-cooled solution ofpyridine-2-amino-3-bromo-5-sulfonic acid (Preparation 7; 25.3 g, 100.0mmol) in aqueous hydrochloric acid (115 mL, 20%), so as to maintain thetemperature below 6° C. The reaction was stirred for 30 minutes at 0° C.and for a further hour at room temperature. The reaction mixture wasevaporated under reduced pressure and the residue dried under vacuum at70° C. for 72 hours. A mixture of this solid, phosphorus pentachloride(30.0 g, 144.0 mmol) and phosphorus oxychloride (1 mL, 10.8 mmol) washeated at 125° C. for 3 hours, and then cooled. The reaction mixture waspoured onto ice (100 g) and the resulting solid filtered, and washedwith water. The product was dissolved in dichloromethane, dried (MgSO₄),and evaporated under reduced pressure to afford the title compound as ayellow solid (26.58 g, 91%).

δ(CDCl₃, 300 MHz): 8.46 (1H, s), 8.92 (1H, s).

Preparation 9 3-Bromo-2-chloro-5-(4-ethylpiperazin-1-ylsulfonyl)pyridine

A solution of 1-ethylpiperazine (11.3 mL, 89.0 mmol) and triethylamine(12.5 mL, 89.0 mmol) in dichloromethane (150 mL) was added dropwise toan ice-cooled solution of pyridine-3-bromo-2-chloro-5-sulfonyl chloride(Preparation 8; 23.0 g, 79.0 mmol) in dichloromethane (150 mL) and thereaction stirred at 0° C. for an hour. The reaction mixture wasconcentrated under reduced pressure and the residual brown oil waspurified by column chromatography on silica gel, using an elutiongradient of dichloromethane:methanol (99:1 to 97:3) to afford the titlecompound as an orange solid (14.5 g, 50%).

δ(CDCl₃, 300 MHz): 1.05 (3H, t), 2.42 (2H, q), 2.55 (4H, m), 3.12 (4H,m), 8.24 (1H, s), 8.67 (1H, s).

Preparation 103-Bromo-2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridine

A mixture of 3-bromo-2-chloro-5-(4-ethylpiperazin-1-ylsulfonyl)pyridine(Preparation 9; 6.60 g, 17.9 mmol) and sodium ethoxide (6.09 g, 89.55mmol) in ethanol (100 mL) was heated under reflux for 18 hours, thencooled. The reaction mixture was concentrated under reduced pressure,the residue partitioned between water (100 mL) and ethyl acetate (100mL), and the layers separated. The aqueous phase was extracted withethyl acetate (2×100 mL), the combined organic solutions dried (MgSO₄)and evaporated under reduced pressure to afford the title compound as abrown solid (6.41 g, 95%).

Anal. Found: C, 41.27; H, 5.33; N, 11.11. C₁₃H₂₀BrN₃O₃S requires C,41.35; H, 5.28; N, 10.99%.

δ(CDCl₃, 300 MHz): 1.06 (3H, t), 1.48 (3H, t), 2.42 (2H, q), 2.56 (4H,m), 3.09 (4H, m), 4.54 (2H, q), 8.10 (1H, s), 8.46 (1H, s).

LRMS: m/z 378, 380 (M+1)⁺.

Preparation 11 Pyridine2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)-3-carboxylic acid ethyl ester

A mixture of 3-bromo-2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridine(Preparation 10; 6.40 g, 16.92 mmol), triethylamine (12 mL, 86.1 mmol),and palladium(0) tetrakis(triphenylphosphine) (1.95 g, 1.69 mmol) inethanol (60 mL) was heated at 100° C. and 1379 kPa (200 psi), under acarbon monoxide atmosphere, for 18 hours, then cooled. The reactionmixture was evaporated under reduced pressure and the residue purifiedby column chromatography on silica gel, using an elution gradient ofdichloromethane: methanol (100:0 to 97:3) to afford the title compoundas an orange oil (6.2 g, 98%).

δ(CDCl₃, 300 MHz): 1.02 (3H, t), 1.39 (3H, t), 1.45 (3H, t), 2.40 (2H,q), 2.54 (4H, m), 3.08 (4H, m), 4.38 (2H, q), 4.55 (2H, q), 8.37 (1H,s), 8.62 (1H, s).

LRMS: m/z 372 (M+1)⁺.

Preparation 12 Pyridine2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)-3-carboxylic Acid

A mixture of pyridine2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)-3-carboxylic acid ethyl ester(Preparation 11; 4.96 g, 13.35 mmol) and aqueous sodium hydroxidesolution (25 mL, 2 N, 50.0 mmol) in ethanol (25 mL) was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated underreduced pressure to half of its original volume, washed with ether andthen acidified to pH 5 using 4 N hydrochloric acid. The aqueous solutionwas extracted with dichloromethane (3×30 mL), which organic extractswere combined, dried (MgSO₄) and then evaporated under reduced pressureto afford the title compound as a tan-coloured solid (4.02 g, 88%).

δ(DMSO-d₆, 300 MHz): 1.18 (3H, t), 1.37 (3H, t), 3.08 (2H, q), 3.17-3.35(8H, m), 4.52 (2H, q), 8.30 (1H, s), 8.70 (1H, s).

Preparation 132-Benzyl-5-(2-n-butoxy-5-iodopyridin-3-ylcarboxamido)-1-n-propyl-imidazole-4-carboxamide

The title compound was obtained in 40% yield from5-amino-2-benzyl-1-n-propylimidazole-4-carboxamide (Preparation 2) and2-n-butoxy-5-iodopyridine-3-carboxylic acid (Preparation 5), followingthe procedure described in Preparation 3.

δ(CDCl₃, 300 MHz): 0.71 (3H, t), 0.96 (3H, t), 1.46 (4H, m), 1.90 (2H,m), 3.83 (2H, t), 4.12 (2H, s), 4.58 (2H, t), 5.25 (1H, s), 6.86 (1H,s), 7.23 (3H, m), 7.34 (2H, m), 8.48 (1H, s), 8.74 (1H, s), 10.26 (1H,s).

LRMS: m/z 562 (M+1)⁺.

Preparation 145-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-ylcarboxamido)-2-methyl-1-n-propylimidazole-4-carboxamide

(i) Benzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexafluorophos-phate (304 mg, 0.58 mmol) was added to a solution ofpyridine 2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)-3-carboxylic acid(Preparation 12; 200 mg, 0.58 mmol) in N,N-dimethylformamide (3 mL), andthe mixture stirred at room temperature for an hour.

(ii) 5-Amino-2-methyl-1-n-propylimidazole-4-carboxamide (Preparation 1;117 mg, 0.64 mmol) was dissolved in hot N,N-dimethylformamide (8 mL),the solution cooled, sodium hydride (22 mg, 60% dispersion in mineraloil, 0.55 mmol) added and the mixture stirred for an hour. Thepreviously prepared solution of activated acid (from (i) above) was thenadded, followed by sodium hydride (22 mg, 60% dispersion in mineral oil,0.55 mmol), and the reaction stirred at room temperature for 3 days, andwarmed to 60° C. for a further 4 days. The cooled mixture was pouredinto 2% aqueous sodium bicarbonate solution (30 mL), and extracted withethyl acetate (2×25 mL). The combined organic extracts were dried(MgSO₄), and evaporated under reduced pressure. The residual gum waspurified by column chromatography on silica gel, eluting withdichloromethane:methanol (92:8), to give the title compound (39 mg,13%).

δ(CDCl₃, 400 MHz): 0.88 (3H, t), 1.02 (3H, t), 1.58 (3H, t), 1.74 (2H,m), 2.40 (5H, m), 2.55 (4H, m), 3.10 (4H, m), 3.95 (2H, t), 4.78 (2H,q), 5.20 (1H, s), 6.77 (1H, s), 8.68 (1H, s), 8.80 (1H, s), 10.42 (1H,s).

LRMS: m/z 508 (M+1)⁺.

Preparation 15 9-(4-Nitrophenyl)-2-(2-n-propoxyphenyl)purin-6-one andPreparation 16 7-(4-Nitrophenyl)-2-(2-n-propoxyphenyl)purin-6-one

A mixture of 2-(2-n-propoxyphenyl)-9H-purin-6-one (prepared as describedin EP 352 960; 570 mg, 2.11 mmol), cesium carbonate (1.37 g, 4.22 mmol)and 1-nitro-4-fluorobenzene (270 μL, 1.76 mmol) in dimethylsulfoxide (15mL) was heated under reflux for 3 hours. The cooled reaction waspartitioned between water and ethyl acetate, and the resultingprecipitate filtered off. The layers of the filtrate were separated, theorganic phase dried (MgSO₄) and evaporated under reduced pressure. Theresulting residue and the filtered solid were combined and purified bycolumn chromatography, eluting with a gradient ofdichloromethane:methanol (100:0 to 90:10), to give the title compound ofPreparation 15 (244 mg, 35%) as the less polar compound,

δ(CDCl₃, 300 MHz): 1.20 (3H, t), 2.04 (2H, m), 4.22 (2H, t), 7.10 (1H,d), 7.20 (1H, m), 7.54 (1H, m), 7.84 (2H, d), 8.20 (1H, s), 8.42 (2H,d), 8.74 (1H, d), 11.70 (1H, s).

LRMS: m/z 392 (M+1)⁺.

followed by the title compound of Preparation 16 (321 mg, 46%) as themore polar compound.

δ(CDCl₃, 300 MHz): 1.18 (3H, t), 2.06 (2H, m), 4.25 (2H, t), 7.15 (2H,m), 7.55 (1H, m), 8.04 (2H, d), 8.15 (1H, s), 8.42 (1H, d), 8.50 (2H,d), 11.62 (1H, s).

Preparation 17 8-Benzyl-2-(2-ethoxyphenyl)-9-n-propylpurin-6-one

Potassium bis(trimethylsilyl)amide (81 mg, 0.40 mmol) was added to asolution of2-benzyl-5-(2-ethoxybenzamido)-1-n-propylimidazole-4-carboxamide(Preparation 3; 110 mg, 0.27 mmol) in ethanol (10 mL), and the reactionheated at 100° C. in a sealed vessel for 18 hours. The cooled mixturewas evaporated under reduced pressure, and the residue purified bycolumn chromatography on silica gel, using an elution gradient ofdichloromethane:methanol (100:0 to 90:10), to afford the title compound(98 mg, 94%).

δ(CDCl₃, 300 MHz): 0.85 (3H, t), 1.64 (5H, m), 3.99 (2H, t), 4.32 (4H,m), 7.02-7.16 (2H, m), 7.28 (5H, m), 7.46 (1H, m), 8.44 (1H, d), 11.30(1H, s).

LRMS: m/z 389 (M+1)⁺.

Preparation 188-Benzyl-2-(2-n-butoxy-5-iodopyridin-3-yl)-9-n-propylpurin-6-one

The title compound was obtained in 87% yield from2-benzyl-5-(2-n-butoxy-5-iodopyridin-3-ylcarboxamido)-1-n-propylimidazole-4-carboxamide(Preparation 13), following the procedure described in Preparation 17.

δ(CDCl₃, 300 MHz): 0.86 (3H, t), 1.00 (3H, t), 1.54 (2H, m), 1.65 (2H,m), 1.94 (2H, m), 4.00 (2H, t), 4.28 (2H, s), 4.59 (2H, t), 7.28 (5H,m), 8.46 (1H, s), 8.95 (1H, s), 11.08 (1H, s).

LRMS: m/z 544 (M+1)⁺.

Preparation 19 2-(2-n-Propoxyphenyl)-8-(pyridin-3-yl)-9H-purin-6-one

A mixture of 5,6-diamino-2-(2-propoxyphenyl)-4 (3H)-pyrimidinone(prepared as described in J. Med. Chem. 18, 1117 (1975); 520 mg, 2.0mmol), 3-pyridinecarboxaldehyde (214 mg, 2.0 mmol) and sodiummetabisulfite (494 mg, 2.6 mmol) in N,N-dimethylacetamide (10 mL) washeated under reflux for 20 hours. The cooled mixture was diluted withwater (50 mL) and extracted with ethyl acetate (3×40 mL). The combinedorganic extracts were filtered, the filtrate washed with brine (3×30mL), dried (MgSO₄) and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel, using anelution gradient of hexane:dichloromethane:methanol (50:50:0 to 0:95:5),to give the title compound as a solid, 172 mg. A sample wasrecrystallised from ethanol:ethyl acetate.

δ(DMSO-d₆, 300 MHz): 1.00 (3H, t), 1.80 (2H, m), 4.10 (2H, t), 7.20 (2H,m), 7.55 (2H, m), 7.80 (1H, m), 8.50 (1H, m), 8.70 (1H, s), 9.35 (1H,s), 11.98 (1H, s), 13.98 (1H, s). m.p. 282-284° C.

Preparation 20 2-(5-Chlorosuphonyl-2-n-propoxyphenyl)-9H-purin-6-one

2-(2-n-Propoxyphenyl)-9H-purin-6-one (prepared as described in EP 352960; 1.08 g, 4.0 mmol) was added to an ice-cooled solution of thionylchloride (2 mL, 27.4 mmol), and chlorosulfonic acid (6 mL, 90.2 mmol),and the reaction mixture was allowed to warm slowly to room temperature,and stirred for a further 18 hours. Ice (15 g) was carefully added, themixture then diluted with water and the resulting precipitate filtered,washed with water, then ether, and dried to give the title compound aswhite solid (1.27 g, 86%).

δ(DMSO-d₆, 300 MHz): 0.98 (3H, t), 1.76 (2H, m), 4.08 (2H, t), 7.15 (1H,d), 7.72 (1H, d), 8.06 (1H, s), 8.80 (1H, s), 9.60-10.08 (1H, br s),12.14-12.40 (1H, br s).

LRMS: m/z 369 (M+1)⁺.

Synthesis of the Compounds of Formulae IA and IB

Example 12-[5-(4-Ethylpiperazin-1-ylsulfonyl)-2-n-propoxphenyl]-9H-purin-6-one

N-Ethylpiperazine (856 μL, 6.74 mmol) was added to a solution of2-(5-chlorosuphonyl-2-n-propoxyphenyl)-9H-purin-6-one (Preparation 20;1.24 g, 3.37 mmol) in ethanol (10 mL), and the reaction stirred at roomtemperature for 18 hours. The mixture was concentrated under reducedpressure, the residue partitioned between dichloromethane and water, andthe layers separated. The aqueous phase was extracted withdichloromethane, the combined organic solutions dried (MgSO₄) andevaporated under reduced pressure. The crude product was triturated withether, the suspension filtered, and the solid dried under vacuum, togive the title compound (1.35 g, 45%).

Anal. Found: C, 52.98; H, 6.44; N, 18.48. C₂₀H₂₆N₆O₄S;0.4H₂O requires C,52.94; H, 5.95; N, 18.52%

δ(DMSO-d₆, 300 MHz): 0.95 (6H, m), 1.78 (2H, m), 2.30 (2H, q), 2.40 (4H,m), 2.89 (4H, m), 4.17 (2H, t), 7.40 (1H, d), 7.82 (1H, d), 7.98 (1H,s), 8.14 (1H, s), 12.00 (1H, brs), 13.20 (1H, br s).

LRMS: m/z 447 (M+1)⁺.

Example 28-Benzyl-2-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)phenyl]-9-n-propyl-purin-6-one

(i) 8-Benzyl-2-[5-chlorosulfonyl-2-ethoxyphenyl]-9-n-propylpurin-6-one

Chlorosulfonic acid (55 μL, 0.82 mmol) was added dropwise to a cooledsolution of 8-benzyl-2-(2-ethoxyphenyl)-9-n-propylpurin-6-one(Preparation 17; 160 mg, 0.41 mmol) in dichloromethane (5 mL), and thereaction stirred at room temperature for 18 hours. The mixture waspoured onto ice, the phases separated, and the aqueous layer extractedwith dichloromethane. The combined organic solutions were evaporatedunder reduced pressure to afford the sub-title compound (74 mg).

(ii)8-Benzyl-2-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)phenyl]-9-n-propylpurin-6-one

N-Ethylpiperazine (73 μL, 0.58 mmol) was added to a solution of8-benzyl-2-[5-chlorosulfonyl-2-ethoxyphenyl]-9-n-propylpurin-6-one (from(i) above; 70 mg, 0.14 mmol) in ethanol (5 mL), and the reaction wasstirred at room temperature for 18 hours. The reaction mixture wasconcentrated under reduced pressure, the residue partitioned betweendichloromethane and sodium bicarbonate solution and the phasesseparated. The organic layer was dried (MgSO₄), and evaporated underreduced pressure. The crude product was purified by columnchromatography on silica gel, using an elution gradient ofdichloromethane:methanol (100:0 to 95:5), to give the title compound (40mg, 17%).

δ(CDCl₃, 400 MHz): 0.84 (3H, t), 1.00 (3H, t), 1.61 (5H, m), 2.38 (2H,q), 2.50 (4H, m), 3.06 (4H, m), 4.00 (2H, t), 4.28 (2H, s), 4.40 (2H,q), 7.17 (1H, s), 7.26 (5H, m), 7.83 (1H, d), 8.80 (1H, s), 11.01 (1H,br s).

LRMS: m/z 565 (M+1)⁺.

Example 32-[5-(4-Ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-9-(4-nitro-phenyl)purin-6-one

(i) 2-[5-Chlorosulfonyl-2-n-propoxyphenyl]-9-(4-nitrophenyl)purin-6-one

9-(4-Nitrophenyl)-2-(2-n-propoxyphenyl)purin-6-one (Preparation 15; 320mg, 0.81 mmol) was dissolved in chlorosulfonic acid (10 mL), and thesolution stirred at room temperature for 18 hours. The mixture waspoured carefully onto ice/water, and the resulting precipitate filtered,and dried to give the sub-title compound (300 mg).

(ii)2-[5-(4-Ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-9-(4-nitro-phenyl)purin-6-one

A mixture of2-[5-chlorosulfonyl-2-n-propoxyphenyl]-9-(4-nitrophenyl)-purin-6-one(from (i) above; 300 mg, 0.61 mmol), N-ethyldiisopropyl-amine (320 μL,1.85 mmol), and N-ethylpiperazine (390 μL, 3.1 mmol) in dichloromethane(10 mL), was stirred at room temperature for 18 hours. The solution waswashed with water, dried (MgSO₄) and concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel, using an elution gradient of dichloromethane:methanol (100:0to 90:10), to afford the title compound (260 mg, 57%).

δ(CDCl₃, 300 MHz): 1.02 (3H, t), 1.20 (3H, t), 2.09 (2H, m), 2.41 (2H,q), 2.55 (4H, m), 3.09 (4H, m), 4.32 (2H, t), 7.21 (1H, d), 7.92 (1H,d), 8.00 (2H, d), 8.18 (1H, s), 8.46 (2H, d), 8.75 (1H, s), 11.20 (1H,s).

LRMS: m/z 568 (M+1)⁺.

Example 49-(4-Aminophenyl)-2-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxy-phenyl]purin-6-one

A mixture of2-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-9-(4-nitrophenyl)purin-6-one(Example 3; 100 mg, 0.176 mmol) and Raney® nickel (50 mg) in n-propanol(5 mL) was hydrogenated at 345 kPa (50 psi) and room temperature for 11hours. The cooled mixture was filtered through Celite®, and the filtrateevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel, using an elution gradient ofdichloromethane:methanol (100:0 to 95:5), to provide the title compound(20 mg, 21%).

δ(CDCl₃, 300 MHz): 1.01 (3H, t), 1.18 (3H, t), 2.04 (2H, m), 2.38 (2H,q), 2.48 (4H, m), 3.03 (4H, m), 3.90 (2H, s), 4.27 (2H, t), 6.80 (2H,d), 7.18 (1H, d), 7.42 (2H, d), 7.85 (1H, d), 7.99 (1H, s), 8.78 (1H,s), 11.08 (1H, s).

LRMS: m/z 538 (M+1)⁺.

Example 52-[5-(4-Methylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-8-(pyridin-3-yl)-9H-purin-6-one

(i)2-[5-Chlorosulfonyl-2-n-propoxyphenyl]-8-(pyridin-3-yl)-9H-purin-6-one

2-(2-n-Propoxyphenyl)-8-(pyridin-3-yl)-9H-purin-6-one (Preparation 19;300 mg, 0.59 mmol) was dissolved in thionyl chloride (189 μL, 2.6 mmol)and chlorosulfonic acid (575 μL, 8.6 mmol) and the reaction stirred atroom temperature for 18 hours. Water was carefully added, and themixture evaporated under reduced pressure to give the crude sulfonylchloride.

(ii)2-[5-(4-Methylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-8-(pyridin-3-yl)-9H-purin-6-one

The residue was suspended in ethanol (2 mL), N-methylpiperazine (653 μL,5.9 mmol) added, and the solution stirred at room temperature for 18hours. The mixture was evaporated under reduced pressure, the residueadsorbed onto silica gel, and purified by column chromatography onsilica gel, eluting with ethyl acetate:ethanol: 0.880 ammonia(70:30:0.3). The product was re-purified by reverse phase columnchromatography on polystyrene resin (MCI gel, from the Mitsubishi KaseiCorporation; CHP 20P; 75-100 Tm), using an elution gradient ofwater:acetonitrile (100:0 to 60:40) to afford the title compound as awhite solid (60 mg, 20%).

δ(CDCl₃, 400 MHz): 1.00 (3H, t), 1.80 (2H, m), 2.17 (3H, s), 2.39 (4H,m), 2.92 (4H, m), 4.20 (2H, t), 7.40 (1H, d), 7.46 (1H, m), 7.80 (1H,d), 8.18 (1H, s), 8.42 (1H, d), 8.55 (1H, m), 9.30 (1H, s), 11.45-11.60(1H, br s).

LRMS: m/z 510 (M+1)⁺.

Example 62-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-8-methyl-9-n-propylpurin-6-one

A mixture of5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-ylcarboxamido)-2-methyl-1-n-propylimidazole-4-carboxamide(Preparation 14; 39 mg, 0.077 mmol) and potassiumbis(trimethylsilyl)amide (30.7 mg, 0.15 mmol) in ethanol (6 mL) washeated at 130° C. in a sealed vessel for 15 hours. The cooled mixturewas concentrated under reduced pressure to a volume of 1 mL, and thendiluted with aqueous sodium bicarbonate solution (15 mL). This wasextracted with ethyl acetate (3×15 mL), the combined organic extractsdried (MgSO₄), and evaporated under reduced pressure. The residual gumwas purified by column chromatography on silica gel, usingdichloromethane:methanol (95:5) as eluant, to give the title compound(25 mg, 65%).

δ(CDCl₃, 300 MHz): 0.94-1.05 (6H, m), 1.59 (3H, t), 1.85 (2H, m), 2.41(2H, q), 2.58 (7H, m), 3.15 (4H, m), 4.17 (2H, t), 4.79 (2H, q), 8.64(1H, s), 9.04 (1H, s), 11.00 (1H, s).

LRMS: m/z 490 (M+1)⁺.

Example 78-Benzyl-2-[2-n-butoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-9-n-propylpurin-6-one

(i) 8-Benzyl-2-[2-n-butoxy-5-sulfanylpyridin-3-yl]-9-n-propylpurin-6-one

A mixture of freshly dried thiourea (78 mg, 1.03 mmol) and8-benzyl-2-(2-n-butoxy-5-iodopyridin-3-yl)-9-n-propylpurin-6-one(Preparation 18; 370 mg, 0.68 mmol) in dry N,N-dimethylformamide (2.75mL) was warmed to 60° C. before bis(triethylphosphine)nickel(II)chloride (25 mg, 0.068 mmol) and sodium cyanoborohydride (6.3 mg, 0.1mmol) were added, and the reaction stirred for 30 minutes. Additionalnickel catalyst (175 mg, 0.47 mmol) and sodium cyanoborohydride (44.1mg, 0.7 mmol) were added and the reaction continued for an hour, thenremoved from the heat. Calcium oxide (55 mg, 0.98 mmol) was added, thereaction stirred for an hour at room temperature and then quenched using1 N hydrochloric acid. The reaction mixture was partitioned betweenethyl acetate and water, and the phases separated. The organic layer waswashed with brine and 1 N hydrochloric acid, dried (MgSO₄) andevaporated under reduced pressure.

(ii)8-Benzyl-2-[2-n-butoxy-5-chlorosulfonylpyridin-3-yl]-9-n-propylpurin-6-one

Potassium nitrate (172 mg, 1.7 mmol) was added to a solution of8-benzyl-2-[2-n-butoxy-5-sulfanylpyridin-3-yl]-9-n-propylpurin-6-one_(from(i) above) in acetonitrile (5 mL), and the solution cooled in anice-bath. Thionyl chloride (140 μL, 1.92 mmol) was added dropwise, andthe reaction stirred at room temperature for 3 hours. The mixture wasconcentrated under reduced pressure, and the residue partitioned betweensodium bicarbonate solution and dichloromethane. The layers wereseparated, and the aqueous layer was extracted with dichioromethane. Thecombined organic solutions were then washed with brine, dried (MgSO₄)and evaporated under reduced pressure.

(iii)8-Benzyl-2-[2-n-butoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-9-n-propylpurin-6-one

8-Benzyl-2-[2-n-butoxy-5-chlorosulfonylpyridin-3-yl]-9-n-propylpurin-6-one(the solid resulting from part (ii) above) was dissolved indichloromethane (5 mL), N-ethyldiisopropylamine (600 μL, 3.47 mmol) andN-ethylpiperazine (430 μL, 3.38 mmol) were added, and the reactionstirred at room temperature for 18 hours. The mixture was concentratedunder reduced pressure, and the residue purified by columnchromatography on silica gel, using an elution gradient ofdichloromethane:methanol (100:0 to 95:5), to afford the title compound(40 mg, 10%).

δ(CDCl₃, 300 MHz): 0.83 (3H, t), 1.00 (6H, m), 1.46-1.70 (4H, m), 1.96(2H, m), 2.40 (2H, q), 2.54 (4H, m), 3.09 (4H, m), 4.00 (2H, t), 4.28(2H, s), 4.68 (2H, t), 7.26 (5H, m), 8.62 (1H, s), 8.99 (1H, s), 10.98(1H, s).

LRMS: m/z 594 (M+1)⁺.

Example 82-(2-n-Propoxy-5-[4-{pyridin-2-yl}piperazin-1-ylsulfonyl]phenyl)-9H-purin-6-one

(i) 2-(5-Chlorosulfonyl-2-n-propoxyphenyl)-9H-purin-6-one

2-(2-n-Propoxyphenyl)-9H-purin-6-one (prepared as described in EP 352960; 1.0 g, 3.69 mmol) was dissolved in ice-cold chlorosulfonic acid (5mL), and the solution stirred at room temperature for 2 hours. Thereaction was cautiously poured onto ice, the resulting precipitatefiltered off, washed with ethyl acetate and ether, and dried undervacuum, to give a solid, 1.0 g.

(ii)2-(2-n-Propoxy-5-[4-{pyridin-2-yl}piperazin-1-ylsulfonyl]phenyl)-9H-purin-6-one

2-(5-Chlorosulfonyl-2-n-propoxyphenyl)-9H-purin-6-one (from (i) above;250 mg) was added to an ice-cold solution of 1-(2-pyridyl)piperazine(294 mg, 1.8 mmol) in ethyl acetate (30 mL), and the reaction thenallowed to warm to room temperature, and stirred for a further 6 hours.The reaction mixture was concentrated under reduced pressure, and theresidue triturated with a methanol/water mixture (50:50). The resultingsolid was filtered, washed with water and ether, and then recrystallisedfrom methanol to afford the title compound as colourless crystals, 207mg. m.p. 186.5-187.5° C.

δ(DMSO-d₆, 300 MHz): 0.95 (3H, t), 1.75 (2H, m), 2.99 (4H, m), 3.60 (4H,m), 4.15 (2H, t), 6.65 (1H, m), 6.80 (1H, d), 7.40 (1H, d), 7.50 (1H,m), 7.85 (1H, d), 8.00 (1H, s), 8.10 (1H, m), 8.20 (1H, s), 12.05 (1H,br s), 13.40 (1H, br s).

Example 92-(2-n-Propoxy-5-[4-{pyridin-2-yl}piperazin-1-ylsulfonyl]phenyl)-9-n-propylpurin-6-one

Sodium hydride (41 mg, 60% dispersion in mineral oil, 1.03 mmol) wasadded to a suspension of2-(2-n-propoxy-5-[4-{pyridin-2-yl}piperazin-1-ylsulfonyl]phenyl)-9H-purin-6-one(Example 8; 230 mg, 0.45 mmol) in tetrahydrofuran (8 mL), and themixture stirred at room temperature under a nitrogen atmosphere for 3hours. 1-Iodopropane (54 μL, 0.54 mmol) was added, and the reactionstirred for 18 hours at room temperature, followed by a further 12 hoursat 60° C. The cooled mixture was poured into water, and extracted withethyl acetate. The combined organic extracts were evaporated underreduced pressure and the crude product purified by column chromatographyon silica gel, eluting with dichloromethane:methanol (97:3), to affordthe title compound (70 mg, 64%).

Anal. Found: C, 57.31; H, 5.90; N, 17.69. C₂₆H₃₁N₇O₄S;0.5H₂O requires C,57.13; H, 5.90; N, 17.94%.

δ(DMSO-d₆, 300 MHz): 0.83 (3H, t), 0.92 (3H, t), 1.70 (2H, m), 1.80 (2H,m), 3.28 (4H, m), 3.59 (4H, m), 4.10 (2H, t), 4.16 (2H, t), 6.61 (1H,m), 6.80 (1H, d), 7.38 (1H, d), 7.50 (1H, m), 7.84 (1H, d), 7.94 (1H,s), 8.04 (1H, m), 8.12 (1H, s), 12.10 (1H, s).

LRMS: m/z 538 (M+1)⁺.

Example 102-[5-(4-Ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-7-n-propylpurin-6-one

Potassium hydroxide (27.6 mg, 0.49 mmol) was added to a solution of2-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-9H-purin-6-one(Example 1; 200 mg, 0.45 mmol) in N,N-dimethylformamide (5 mL), and themixture stirred at room temperature for 4 hours, then cooled in anice-bath. 1-Iodopropane (76.1 mg, 0.45 mmol) was added, the reactionstirred at 5° C. for 3 hours, and then for a further 18 hours at roomtemperature. The reaction mixture was concentrated under reducedpressure, the residue suspended in water, and extracted withdichloromethane (x 2). The combined organic extracts were dried (MgSO₄)and evaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel, using an elution gradient ofdichloromethane:methanol (98:2 to 96:4), and azeotroped withdichloromethane, to afford the title compound as a white solid (70 mg,32%).

δ(CDCl₃, 300 MHz): 1.00 (6H, m), 1.20 (3H, t), 1.94-2.12 (4H, m), 2.40(2H, m), 2.54 (4H, m), 3.10 (4H, m), 4.26 (2H, t), 4.38 (2H, t), 7.17(1H, d), 7.84 (2H, m), 9.03 (1H, s), 11.12 (1H, s).

LRMS: m/z 489 (M+1)⁺.

Example 112-[5-(4-Ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-7-(4-nitro-phenyl)purin-6-one

The title compound was obtained in 60% yield from7-(4-nitrophenyl)-2-(2-n-propoxyphenyl)purin-6-one (Preparation 16) andN-ethylpiperazine, following the procedure described in Example 3.

δ(CDCl₃, 300 MHz): 1.02 (3H, t), 1.20 (3H, t), 2.07 (2H, m), 2.40 (2H,q), 2.57 (4H, m), 3.13 (4H, m), 4.32 (2H, t), 7.20 (1H, d), 7.88 (3H,m), 8.22 (1H, s), 8.42 (2H, d), 9.04 (1H, s), 11.40 (1H, s).

LRMS: m/z 568 (M+1)⁺.

Example 127-(4-Aminophenyl)-2-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxy-phenyl]purin-6-one

Iron powder (137 mg, 2.45 mmol) was added to a solution of2-[5-(4-ethylpiperazin-1-ylsulfonyl)-2-n-propoxyphenyl]-7-(4-nitrophenyl)purin-6-one(Example 11; 110 mg, 0.19 mmol) in acetic acid (2.2 mL) and water (100μL), and the reaction stirred vigorously at room temperature for 3hours. The mixture was filtered through Celite®, washing well with ethylacetate, and the filtrate concentrated under reduced pressure. Theresidue was partitioned between ethyl acetate and sodium bicarbonatesolution, the layers separated, and the organic phase dried (MgSO₄) andevaporated under reduced pressure to give the title compound (80 mg,79%).

δ(CDCl₃, 300 MHz): 1.06-1.24 (6H, m), 2.03 (2H, m), 2.50-2.80 (6H, m),3.21 (4H, m), 3.90 (2H, s), 4.26 (2H, t), 6.78 (2H, d), 7.18 (1H, d),7.35 (2H, d), 7.86 (1H, d), 8.03 (1H, s), 9.05 (1H, s), 11.21 (1H, s).

LRMS: m/z 538 (M+1)⁺.

Biological Activity

Compounds of the invention were found to have in vitro activities asinhibitors of cGMP PDE5 with IC₅₀ values of less than about 100 nM.

The following Table illustrates the in vitro activities for a range ofcompounds of the invention as inhibitors of cGMP PDE5.

Example number Concentration (nM) Percentage inhibition of PDE 5 1 10047 4 10 74.1 5 100 48 7 10 80.3 9 10 100

Abbreviations

The following abbreviations may be used herein:

Ac = acetyl aq. = aqueous br = broad (in relation to NMR) d = doublet(in relation to NMR) DCM = dichloromethane dd = doublet of doublets (inrelation to NMR) DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide Et= ethyl EtOAc = ethyl acetate h = hour(s) HPLC = high performance liquidchromatography IMS = industrial methylated spirits IPA = iso-propylalcohol (propan-2-ol) LRMS = low resolution mass spectrometry m =multiplet (in relation to NMR) Me = methyl MeCN = acetonitrile MeOH =methanol min. = minute(s) m.p. = melting point MS = mass spectroscopyOAc = acetate q = quartet (in relation to NMR) rt = room temperature s =singlet (in relation to NMR) t = triplet (in relation to NMR) THF =tetrahydrofuran

What is claimed is:
 1. A compound of formula IA,

wherein X represents CH or N; R¹ represents H, —CN, —C(O)N(R⁴)R⁵,—C(O)R⁴, —C(O)OR⁴, —N(R⁴)R⁶, —OR⁷, aryl, Het² or lower alkyl optionallyinterrupted by one or more of —O—, —S— or —N(R⁴)— and/or substitutedand/or terminated by one or more substituents selected from the groupconsisting of halo, —CN, —NO₂, lower alkyl, —C(O)N(R⁴)R⁵, —C(O)R⁴,—C(O)OR⁴, —N(R⁴)R⁶, —OR⁷, —S(O)_(n)R⁴, —S(O)_(n)N(R⁴)R⁵, aryl and Het²;R⁶ represents R⁵, —S(O)₂R⁸, —S(O)₂N(R⁴)R⁵, —C(O)R⁴, —C(O)OR⁸ or—C(O)N(R⁴)R⁵; R⁷ represents R⁴ or —C(O)R⁴; R³, R⁴, R⁵ and R⁸independently represent, at each occurrence, lower alkyl optionallysubstituted and/or terminated by one or more substituents selected fromthe group consisting of lower alkyl, aryl, Het³, halo, —CN, —NO₂,—OR^(9a), —C(O)R^(9b), —C(O)OR^(9c), —C(O)N(R^(9d))R^(9e),—S(O)₂R^(10a), —S(O)₂N(R^(9f))R^(9g), —OC(O)R^(9h) and —N(R¹¹)R^(9i);R³, R⁴ and R⁵ may also, at each occurrence, independently represent H;R⁴, R⁵ and R⁸ may also, at each occurrence, independently representaryl; R² represents H, aryl, Het⁴ or lower alkyl optionally substitutedby one or more substituents selected from the group consisting of loweralkyl optionally substituted by one or more substituents selected from—OH or halo, aryl, Het⁵, halo, —CN, —NO₂, —OR^(9a), —C(O)R^(9b),—C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), —S(O)₂R^(10a),—S(O)₂N(R^(9f))R^(9g), —OC(O)R^(9h) and —N(R¹¹)R^(9i); R¹¹ represents,at each occurrence, H, aryl, lower alkyl optionally substituted by oneor more substituents selected from the group consisting of aryl andhalo, —C(O)R^(9j), —C(O)N(R^(9k))R^(9m) or —S(O)₂R^(10b); R^(9a) toR^(9m) independently represent, at each occurrence, H, aryl or loweralkyl optionally substituted by one or more substituents selected fromthe group consisting of aryl and halo; R^(10a) and R^(10b) represent, ateach occurrence, aryl or lower alkyl optionally substituted by one ormore substituents selected from the group consisting of aryl and halo;Het¹ represents an optionally substituted four- to twelve-memberedheterocyclic group, which group contains at least one nitrogen atom bywhich the Het¹ group is attached to the compound and, optionally, one ormore further heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur; Het² to Het⁵ independently represent optionallysubstituted four- to twelve-membered heterocyclic groups, which groupscontain one or more heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur; each aryl group is optionally substitutedwith one or more substituents selected from the group consisting ofhalo, lower alkyl optionally substituted by one or more substituentsselected from —CN, —NO₂, —OR^(9a), —C(O)R^(9b), —C(O)OR^(9c),—C(O)N(R^(9d))R^(9e), —S(O)₂N(R^(9f))R^(9g), —S(O)_(n)R^(10a),—OC(O)R^(9h) or —N(R¹¹)R^(9i)), —CN, —NO₂, —OR^(9a), —C(O)R^(9b),—C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), —S(O)_(n)R^(10a),—S(O)₂N(R^(9f))R^(9g), —OC(O)R^(9h) and —N(R¹¹)R^(9i); Het¹, Het², Het³,Het⁴ and Het⁵ are each optionally substituted with one or moresubstituents selected from the group consisting of lower alkyloptionally substituted by one or more substituents selected from loweralkyl, aryl, Het², halo, —CN, —NO₂, —OR^(9a), —C(O)R^(9b), —C(O)OR^(9c),—C(O)N(R^(9d))R^(9e), —S(O)_(n)R^(10a), —S(O)₂N(R^(9f))R^(9g),—OC(O)R^(9h) or —N(R¹¹)R^(9i)), aryl, Het², halo, —CN, —NO₂, —OR^(9a),—C(O)R^(9b), —C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), —S(O)_(n)R^(10a),—S(O)₂N(R^(9f))R^(9g), —OC(O)R^(9h) and —N(R¹¹)R^(9i); and n represents,at each occurrence, 0, 1 or 2; or a pharmaceutically, or a veterinarily,acceptable solvate or prodrug therefor.
 2. A compound as defined inclaim 1 wherein at least one of the following applies: (1) R¹ represents—CN, —C(O)N(R⁴)R⁵, —C(O)R⁴, —C(O)OR⁴, —N(R⁴)R⁶, —OR⁷, aryl, Het² orlower alkyl optionally interrupted by one or more of —O—, —S— or —N(R⁴)—substituted by one or more substituents selected from the groupconsisting of halo, —CN, —NO₂, lower alkyl, —C(O)N(R⁴)R⁵, —C(O)R⁴,—C(O)OR⁴, —N(R⁴)R⁶, —OR⁷, —S(O)_(n)R⁴ or —S(O)_(n)N(R⁴)R⁵, aryl andHet²; (2) R² represents H, aryl, Het⁴, C₁₋₂ alkyl substituted by one ormore substituents selected from the group consisting of aryl, —OR^(9a),—C(O)R^(9b), —OC(O)R^(9h) and —N(R¹¹)R^(9i) or lower alkyl substitutedby: (i) one or more substituents selected from the group consisting ofhalo, —CN, —NO₂, Het⁵, —OR^(9a), —C(O)R^(9b) wherein R^(9a) and R^(9b)represent aryl or lower alkyl substituted by one or more halo atoms—C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), —S(O)₂R^(10a), —S(O)₂N(R^(9f))R^(9g)and —N(R¹¹)R^(9i) wherein R¹¹ represents aryl or —C(O)N(R^(9k))R^(9m));or (ii) more than one substituent selected from the group consisting of—OR^(9a) wherein R^(9a) represents aryl or lower alkyl optionallysubstituted by one or more substituents selected from aryl or halo,—C(O)R^(9b), —OC(O)R^(9h) and —N(R¹¹)R^(9i); (3) R³ represents H orlower alkyl substituted by one or more substituents selected from thegroup consisting of aryl, Het³, halo, —CN, —NO₂, —OR^(9a), —C(O)R^(9b),—C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), —S(O)₂R^(10a),—S(O)₂N(R^(9f))R^(9g), —OC(O)R^(9h) and —N(R¹¹)R^(9i); (4) Het¹represents: (i) a 4- or 7- to 12-membered optionally substitutedheterocyclic group as defined in claim 1; (ii) a 5- or 6-membered fullysaturated heterocyclic group as defined in claim 1, which group is notsubstituted by C₁₋₆ alkyl optionally substituted by —OH; or (iii) a 5-or 6-membered optionally substituted, partly unsaturated or aromaticheterocyclic group as defined in claim 1; or (5) X represents N;wherein, unless otherwise specified, substituents n, R⁴, R⁵, R⁶, R⁷,R^(9a) to R^(9m), R^(10a), R¹¹, Het², Het⁴ and Het⁵ are as defined inclaim
 1. 3. A compound as defined in claim 1 wherein at least one of thefollowing applies: (1) R¹ represents —CN, —C(O)N(R⁴)R⁵, —C(O)R⁴,—C(O)OR⁴, —N(R⁴)R⁶, —OR⁷, aryl, Het² or lower alkyl optionallyinterrupted by one or more of —O—, —S— or —N(R⁴)— or substituted by oneor more substituents selected from the group consisting of halo, —CN,—NO₂, lower alkyl, —C(O)N(R⁴)R⁵, —C(O)R⁴, —C(O)OR⁴, —N(R⁴)R⁶, —OR⁷,—S(O)_(n)R⁴, —S(O)_(n)N(R⁴)R⁵, aryl and Het²; (2) R² represents H, aryl,Het⁴, C₁₋₂ alkyl substituted by one or more substituents selected fromthe group consisting of aryl, —OR^(9a), —C(O)R^(9b), —OC(O)R^(9h), and—N(R¹¹)R^(9i)), or lower alkyl substituted by: (i) one or moresubstituents selected from the group consisting of halo, —CN, —NO₂,Het⁵, —OR^(9a), —C(O)R^(9b) wherein R^(9a) and R^(9b) represent aryl orlower alkyl substituted by one or more halo atoms, —C(O)OR^(9c),—C(O)N(R^(9d))R^(9e), —S(O)₂R^(10a), —S(O)₂N(R^(9f))R^(9g) and—N(R¹¹)R^(9i) wherein R¹¹ represents aryl or —C(O)N(R^(9k))R^(9m)); or(ii) more than one substituent selected from the group consisting of—OR^(9a) wherein R^(9a) represents aryl or lower alkyl optionallysubstituted by one or more substituents selected from aryl or halo,—C(O)R^(9b), —OC(O)R^(9h) and —N(R¹¹)R^(9i); (3) R³ represents H orlower alkyl substituted by one or more substituents selected from thegroup consisting of aryl, Het³, halo, —CN, —NO₂, OR^(9a), —C(O)R^(9b),—C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), —S(O)₂R^(10a),—S(O)₂N(R^(9f))R^(9g), —OC(O)R^(9h), and —N(R¹¹)R^(9i); (4) Het¹represents: (i) a 4- or 7- to 12-membered optionally substitutedheterocyclic group as defined in claim 1; (ii) a 5- or 6-membered fullysaturated heterocyclic group as defined in claim 1, which group is notsubstituted by C₁₋₆ alkyl optionally substituted by —OH; or (iii) a 5-or 6-membered optionally substituted, partly unsaturated or aromaticheterocyclic group as defined in claim 1; or (5) X represents N;wherein, unless otherwise specified, substituents n, R⁴, R⁵, R⁶, R⁷,R^(9a) to R^(9m), R^(10a), R¹¹, Het², Het⁴ and Het⁵ are as defined inclaim
 1. 4. A compound of claim 1, wherein R¹ represents H, —CN,—C(O)N(R⁴)R⁵, —C(O)R⁴, —C(O)OR⁴, —N(R⁴)R⁶, —OR⁷, aryl, Het² or C₁₋₆alkyl optionally substituted by one or more substituents selected fromthe group consisting of halo, —CN, —NO₂, lower alkyl, —C(O)N(R⁴)R⁵,—C(O)R⁴, —C(O)OR⁴, —N(R⁴)R⁶, —OR⁷, —S(O)_(n)R⁴, —S(O)_(n)N(R⁴)R⁵, aryland Het².
 5. A compound of claim 1, wherein R⁶ represents R⁵, —S(O)₂R⁸or —C(O)R⁴.
 6. A compound of claim 1 wherein R⁷ represents R⁴.
 7. Acompound of claim 1, wherein R³, R⁴, R⁵ and R⁸ independently representlower alkyl, optionally substituted by one or more substituents selectedfrom from the group consisting of aryl, Het³, halo, —CN, —NO₂, —OR^(9a),—N(R¹¹)R^(9i); R³, R⁴ and R⁵ independently represent H; or R⁴, R⁵ and R⁸independently represent aryl.
 8. A compound of claim 1 wherein R²represents H, aryl, Het⁴ or lower alkyl optionally substituted by one ormore substituents selected from halo, —CN, —NO₂, aryl, Het⁵, —OR^(9a),C(O)R^(9b), —C(O)OR^(9c), —C(O)N(R^(9d))R^(9e), —S(O)_(n)R^(10a),—S(O)₂N(R^(9f))R^(9g) or —N(R¹¹)R^(9i).
 9. A compound of claim 1 whereinn represents 0 or
 2. 10. A compound of claim 1 wherein R¹¹ represents H,C₁₋₆ alkyl or —C(O)R^(9j).
 11. A compound of claim 1 wherein R^(9a) toR^(9j) independently represent H or C₁₋₆ alkyl.
 12. A compound of claim1 wherein R^(10a) represents C₁₋₆ alkyl.
 13. A compound of claim 1wherein Het¹ represents a four- to seven-membered heterocyclic group,which group contains at least one nitrogen atom by which the Het¹ groupis attached to the rest of the compound and, optionally, one or morefurther heteroatoms selected from the group consisting of nitrogen andoxygen, and is optionally substituted as defined in claim
 1. 14. Acompound of claim 1 wherein Het² to Het⁵ independently represent four-to ten-membered heterocyclic groups containing between one and fourheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and which groups are optionally substituted as defined inclaim
 1. 15. A pharmaceutical formulation comprising a compound of claim1 and a pharmaceutically acceptable adjuvant, diluent or carrier.
 16. Aveterinary formulation comprising a compound of claim 1 and aveterinarily acceptable adjuvant, diluent or carrier.
 17. A method oftreating or preventing a medical condition for which inhibition of cGMPPDE5 is desired, which comprises administering a therapeuticallyeffective amount of a compound of claim 1 to a patient in need of suchtreatment.
 18. The method of claim 17, wherein the condition is maleerectile dysfunction, impotence, female sexual dysfunction, clitoraldysfunction, female hypoactive sexual desire disorder, female sexualarousal disorder, female sexual pain disorder or female sexual orgasmicdysfunction.
 19. The method of claim 17, wherein the condition is maleerectile dysfunction.